Food Insecurity and Hypoglycemia among Older Patients with Type 2 Diabetes Treated with Insulin or Sulfonylureas: The Diabetes & Aging Study.

BACKGROUND: Severe hypoglycemia is a serious adverse drug event associated with hypoglycemia-prone medications; older patients with diabetes are particularly at high risk. Economic food insecurity (food insecurity due to financial limitations) is a known risk factor for hypoglycemia; however, less is known about physical food insecurity (due to difficulty cooking or shopping for food), which may increase with age, and its association with hypoglycemia. OBJECTIVE: Study associations between food insecurity and severe hypoglycemia. DESIGN: Survey based cross-sectional study. PARTICIPANTS: Survey responses were collected in 2019 from 1,164 older (≥ 65 years) patients with type 2 diabetes treated with insulin or sulfonylureas. MAIN MEASURES: Risk ratios (RR) for economic and physical food insecurity associated with self-reported severe hypoglycemia (low blood glucose requiring assistance) adjusted for age, financial strain, HbA1c, Charlson comorbidity score and frailty. Self-reported reasons for hypoglycemia endorsed by respondents. KEY RESULTS: Food insecurity was reported by 12.3% of the respondents; of whom 38.4% reported economic food insecurity only, 21.1% physical food insecurity only and 40.5% both. Economic food insecurity and physical food insecurity were strongly associated with severe hypoglycemia (RR = 4.3; p = 0.02 and RR = 4.4; p = 0.002, respectively). Missed meals ("skipped meals, not eating enough or waiting too long to eat") was the dominant reason (77.5%) given for hypoglycemia. CONCLUSIONS: Hypoglycemia prevention efforts among older patients with diabetes using hypoglycemia-prone medications should address food insecurity. Standard food insecurity questions, which are used to identify economic food insecurity, will fail to identify patients who have physical food insecurity only.

Association of Real-time Continuous Glucose Monitoring With Glycemic Control and Acute Metabolic Events Among Patients With Insulin-Treated Diabetes.

Importance: Continuous glucose monitoring (CGM) is recommended for patients with type 1 diabetes; observational evidence for CGM in patients with insulin-treated type 2 diabetes is lacking. Objective: To estimate clinical outcomes of real-time CGM initiation. Design, Setting, and Participants: Exploratory retrospective cohort study of changes in outcomes associated with real-time CGM initiation, estimated using a difference-in-differences analysis. A total of 41 753 participants with insulin-treated diabetes (5673 type 1; 36 080 type 2) receiving care from a Northern California integrated health care delivery system (2014-2019), being treated with insulin, self-monitoring their blood glucose levels, and having no prior CGM use were included. Exposures: Initiation vs noninitiation of real-time CGM (reference group). Main Outcomes and Measures: Ten end points measured during the 12 months before and 12 months after baseline: hemoglobin A1c (HbA1c); hypoglycemia (emergency department or hospital utilization); hyperglycemia (emergency department or hospital utilization); HbA1c levels lower than 7%, lower than 8%, and higher than 9%; 1 emergency department encounter or more for any reason; 1 hospitalization or more for any reason; and number of outpatient visits and telephone visits. Results: The real-time CGM initiators included 3806 patients (mean age, 42.4 years [SD, 19.9 years]; 51% female; 91% type 1, 9% type 2); the noninitiators included 37 947 patients (mean age, 63.4 years [SD, 13.4 years]; 49% female; 6% type 1, 94% type 2). The prebaseline mean HbA1c was lower among real-time CGM initiators than among noninitiators, but real-time CGM initiators had higher prebaseline rates of hypoglycemia and hyperglycemia. Mean HbA1c declined among real-time CGM initiators from 8.17% to 7.76% and from 8.28% to 8.19% among noninitiators (adjusted difference-in-differences estimate, -0.40%; 95% CI, -0.48% to -0.32%; P < .001). Hypoglycemia rates declined among real-time CGM initiators from 5.1% to 3.0% and increased among noninitiators from 1.9% to 2.3% (difference-in-differences estimate, -2.7%; 95% CI, -4.4% to -1.1%; P = .001). There were also statistically significant differences in the adjusted net changes in the proportion of patients with HbA1c lower than 7% (adjusted difference-in-differences estimate, 9.6%; 95% CI, 7.1% to 12.2%; P < .001), lower than 8% (adjusted difference-in-differences estimate, 13.1%; 95% CI, 10.2% to 16.1%; P < .001), and higher than 9% (adjusted difference-in-differences estimate, -7.1%; 95% CI, -9.5% to -4.6%; P < .001) and in the number of outpatient visits (adjusted difference-in-differences estimate, -0.4; 95% CI, -0.6 to -0.2; P < .001) and telephone visits (adjusted difference-in-differences estimate, 1.1; 95% CI, 0.8 to 1.4; P < .001). Initiation of real-time CGM was not associated with statistically significant changes in rates of hyperglycemia, emergency department visits for any reason, or hospitalizations for any reason. Conclusions and Relevance: In this retrospective cohort study, insulin-treated patients with diabetes selected by physicians for real-time continuous glucose monitoring compared with noninitiators had significant improvements in hemoglobin A1c and reductions in emergency department visits and hospitalizations for hypoglycemia, but no significant change in emergency department visits or hospitalizations for hyperglycemia or for any reason. Because of the observational study design, findings may have been susceptible to selection bias.

Continuous Glucose Monitor Metrics Are Associated with Emergency Department Visits and Hospitalizations for Hypoglycemia and Hyperglycemia, but Have Low Predictive Value.

Objective: Determine whether continuous glucose monitor (CGM) metrics can provide actionable advance warning of an emergency department (ED) visit or hospitalization for hypoglycemic or hyperglycemic (dysglycemic) events. Research Design and Methods: Two nested case-control studies were conducted among insulin-treated diabetes patients at Kaiser Permanente, who shared their CGM data with their providers. Cases included dysglycemic events identified from ED and hospital records (2016-2021). Controls were selected using incidence density sampling. Multiple CGM metrics were calculated among patients using CGM >70% of the time, using CGM data from two lookback periods (0-7 and 8-14 days) before each event. Generalized estimating equations were specified to estimate odds ratios and C-statistics. Results: Among 3626 CGM users, 108 patients had 154 hypoglycemic events and 165 patients had 335 hyperglycemic events. Approximately 25% of patients had no CGM data during either lookback; these patients had >2 × the odds of a hypoglycemic event and 3-4 × the odds of a hyperglycemic event. While several metrics were strongly associated with a dysglycemic event, none had good discrimination. Conclusion: Several CGM metrics were strongly associated with risk of dysglycemic events, and these can be used to identify higher risk patients. Also, patients who are not using their CGM device may be at elevated risk of adverse outcomes. However, no CGM metric or absence of CGM data had adequate discrimination to reliably provide actionable advance warning of an event and thus justify a rapid intervention.

Race and ethnicity and pharmacy dispensing of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

Background: Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) improve cardiorenal outcomes in patients with type 2 diabetes. Equitable use of SGLT2i and GLP-1 RA has the potential to reduce racial and ethnic health disparities. We evaluated trends in pharmacy dispensing of SGLT2i and GLP-1 RA by race and ethnicity. Methods: Retrospective cohort study of patients (≥18 years) with type 2 diabetes using 2014-2022 electronic health record data from six US care delivery systems. Entry was at earliest pharmacy dispensing of any type 2 diabetes medication. We used multivariable logistic regression to evaluate the association between pharmacy dispensing of SGLT2i and GLP1-RA and race and ethnicity. Findings: Our cohort included 687,165 patients (median 6 years of dispensing data; median 60 years; 0.3% American Indian/Alaska Native (AI/AN), 16.6% Asian, 10.5% Black, 1.4% Hawaiian or Pacific Islander (HPI), 31.1% Hispanic, 3.8% Other, and 36.3% White). SGLT2i was lower for AI/AN (OR 0.80, 95% confidence interval 0.68-0.94), Black (0.89, 0.86-0.92) and Hispanic (0.87, 0.85-0.89) compared to White patients. GLP-1 RA was lower for AI/AN (0.78, 0.63-0.97), Asian (0.50, 0.48-0.53), Black (0.86, 0.83-0.90), HPI (0.52, 0.46-0.57), Hispanic (0.69, 0.66-0.71), and Other (0.78, 0.73-0.83) compared to White patients. Interpretation: Dispensing of SGLT2is, and GLP-1 RAs was lower in minority group patients. There is a need to evaluate approaches to increase use of these cardiorenal protective drugs in patients from racial and ethnic minority groups with type 2 diabetes to reduce adverse cardiorenal outcomes and improve health equity. Funding: Patient-Centered Outcomes Research Institute and National Institutes of Health.

Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes.

Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.

Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for Diabetes in Youth Study.

BACKGROUND: Neonatal diabetes mellitus (NDM) is defined as diabetes with onset before 6 months of age. Nearly half of individuals with NDM are affected by permanent neonatal diabetes mellitus (PNDM). Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of PNDM. OBJECTIVE: To estimate the prevalence of PNDM among SEARCH for Diabetes in Youth (SEARCH) study participants (2001-2008) and to identify the genetic mutations causing PNDM. METHODS: SEARCH is a multicenter population-based study of diabetes in youth <20 yr of age. Participants diagnosed with diabetes before 6 months of age were invited for genetic testing for mutations in the KCNJ11, ABCC8, and INS genes. RESULTS: Of the 15,829 SEARCH participants with diabetes, 39 were diagnosed before 6 months of age. Thirty-five of them had PNDM (0.22% of all diabetes cases in SEARCH), 3 had transient neonatal diabetes that had remitted by 18 months and 1 was unknown. The majority of them (66.7%) had a clinical diagnosis of type1 diabetes by their health care provider. Population prevalence of PNDM in youth <20 yr was estimated at 1 in 252 000. Seven participants underwent genetic testing; mutations causing PNDM were identified in five (71%), (two KCNJ11, three INS). CONCLUSIONS: We report the first population-based frequency of PNDM in the US based on the frequency of PNDM in SEARCH. Patients with NDM are often misclassified as having type1 diabetes. Widespread education is essential to encourage appropriate genetic testing and treatment of NDM.

Racial and Ethnic Differences in the Association Between Mean Glucose and Hemoglobin A1c.

Background: Studies have reported significantly higher hemoglobin A1c (A1C) in African American patients than in White patients with the same mean glucose, but less is known about other racial/ethnic groups. We evaluated racial/ethnic differences in the association between mean glucose, based on continuous glucose monitor (CGM) data, and A1C. Methods: Retrospective study among 1788 patients with diabetes from Kaiser Permanente Northern California (KPNC) who used CGM devices during 2016 to 2021. In this study population, there were 5264 A1C results; mean glucose was calculated from 124,388,901 CGM readings captured during the 90 days before each A1C result. Hierarchical mixed models were specified to estimate racial/ethnic differences in the association between mean glucose and A1C. Results: Mean A1C was 0.33 (95% confidence interval: 0.23-0.44; P < 0.0001) percentage points higher among African American patients relative to White patients for a given mean glucose. A1C results for Asians, Latinos, and multiethnic patients were not significantly different from those of White patients. The slope of the association between mean glucose and A1C did not differ significantly across racial/ethnic groups. Variance for the association between mean glucose and A1C was substantially greater within groups than between racial/ethnic groups (65% vs. 9%, respectively). Conclusions: For African American patients, A1C results may overestimate glycemia and could lead to premature diabetes diagnoses, overtreatment, or invalid assessments of health disparities. However, most of the variability in the mean glucose-A1C association was within racial/ethnic groups. Treatment decisions driven by guideline-based A1C targets should be individualized and supported by direct measurement of glycemia.

Quantification of risk factors for diabetic retinopathy progression.

AIMS: To determine the importance of blood sugar control, blood pressure, and other key systemic factors on the risk of progression from no retinopathy to various stages of diabetic retinopathy. METHODS: Restrospective cohort analysis of patients (N = 99, 280) in the Kaiser Permanente Northern California healthcare system with a baseline retina photographic screening showing no evidence of retinopathy and a minimum follow-up surveillance period of 3 years from 2008 to 2019. We gathered longitudinal data on diabetic retinopathy progression provided by subsequent screening fundus photographs and data captured in the electronic medical record over a mean surveillance of 7.3 ± 2.2 (mean ± SD) years. Progression from an initial state of no diabetic retinopathy to any of four outcomes was determined: (1) any incident retinopathy, (2) referable (moderate or worse) retinopathy, (3) diabetic macular edema, and (4) proliferative diabetic retinopathy. Multiple predictors, including age, race, gender, glycosylated hemoglobin (HbA1c), systolic blood pressure (SBP), cholesterol, chronic renal disease, and type of diabetes were investigated. RESULTS: Among modifiable risk factors, the average HbA1c had the strongest impact on the progression of diabetic retinopathy, followed by average SBP control and total cholesterol. Patients with an average HbA1c of 10.0% or greater (≥ 97 mmol/mol) had a risk ratio of 5.72 (95% CI 5.44-6.02) for progression to any retinopathy, 18.84 (95% CI 17.25-20.57) for referable retinopathy, 22.85 (95% CI 18.87-27.68) for diabetic macular edema, and 25.96 (95% CI 18.75-36.93) for proliferative diabetic retinopathy compared to those with an average HbA1c of 7.0% (53 mmol/mol) or less. Non-white patients generally had a higher risk of progression to all forms of diabetic retinopathy, while Asian patients were less likely to develop diabetic macular edema (HR 0.76, 95% CI 0.66-0.87). CONCLUSIONS: We confirm the critical importance of glucose control as measured by HbA1c on the risk of development of diabetic retinopathy.

Continuous Glucose Monitor Use Prevents Glycemic Deterioration in Insulin-Treated Patients with Type 2 Diabetes.

Continuous glucose monitoring (CGM) is indicated in poorly controlled insulin-treated patients with type 2 diabetes (T2D) to improve glycemic control and reduce the risk of hypoglycemia, but the benefits of CGM for lower risk patients have not been well studied. Among 17,422 insulin-treated patients with T2D with hemoglobin A1c (HbA1c) <8% and no recent severe hypoglycemia (based on emergency room visits or hospitalizations), CGM initiation occurred in 149 patients (17,273 noninitiators served as reference). Changes in HbA1c and severe hypoglycemia rates for the 12 months before and after CGM initiation were calculated. CGM initiation was associated with decreased HbA1c (-0.06%), whereas noninitiation was associated with increased HbA1c (+0.32%); a weighted adjusted difference-in-difference model of change in HbA1c yielded a net benefit of -0.30%; 95% CI -0.50%, -0.10%; P = 0.004). No significant differences were observed for severe hypoglycemia. CGM may be useful in preventing glycemic deterioration in well-controlled patients with insulin-treated T2D.

Continuous glucose monitoring and intensive treatment of type 1 diabetes.

BACKGROUND: The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS: In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS: The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS: Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes.

Autoantibodies to glutamate decarboxylase 65 (GAD65Ab) are commonly believed to be a major characteristic for type 1 diabetes (T1D). We investigated the presence of GAD65Ab in healthy individuals (n = 238) and first-degree relatives (FDRs) of T1D patients (n = 27) who tested negative for GAD65Ab in conventional RIAs. Sera were applied to affinity columns coated with GAD65-specific mAbs to absorb anti-idiotypic antibodies (anti-Ids). The absorbed sera were analyzed for binding to GAD65 by RIAs. Both healthy individuals and FDRs present GAD65Ab that are inhibited by anti-Id, masking them in conventional detection methods. The presence of GAD65Ab-specific anti-Ids was confirmed by competitive ELISA. Remarkably, T1D patients (n = 54) and Stiff Person Syndrome patients (n = 8) show a specific lack of anti-Ids to disease-associated GAD65Ab epitopes. Purified anti-Ids from healthy individuals and FDRs inhibited the binding of GAD65Ab from T1D patients to GAD65. We conclude that masked GAD65Ab are present in the healthy population and that a lack of particular anti-Ids, rather than GAD65Ab per se, is a characteristic of T1D. The lack of these inhibitory antibodies may contribute to T cell activation by GAD65Ab.

Practical aspects of real-time continuous glucose monitoring.

The advent of commercially available real-time (rt) continuous glucose monitoring (CGM) is revolutionizing diabetes care. This technology, which allows patients to view an approximation of their blood glucose (BG) levels every 5 min, permits fine-tuning of a patient's glycemic control that is not possible with self-monitoring of BG. While at first glance this technology seems too good to be true, it is still early in its development, and thus some practical aspects of its use must be considered before recommending rt-CGM to every patient with diabetes. Every clinician who prescribes these devices needs to understand the balance between the potential for improving diabetes control, the safety features, the economic implications, and the patient factors, all of which impact the decision to prescribe rt-CGM for an individual patient. In this review, we will discuss the practical benefits and challenges of rt-CGM use, in order to better educate care providers as to which of their patients might actually benefit from this technology.

Clinical Response to Real-Time Patient-Reported Diabetic Peripheral Neuropathy Symptoms.

INTRODUCTION: To assess clinician response to real-time patient-reported data about diabetic peripheral neuropathy (DPN) symptoms, we analyzed DPN diagnosis and treatment patterns after administration of a 4-question symptom questionnaire in a large vertically integrated health care system. METHODS: Retrospective cohort study to analyze data from 160,852 patients screened for DPN symptoms from April 2012 to March 2014. Electronic medical record data were used to study changes in DPN diagnosis, treatment initiation, and treatment intensification. We used logistic regression to study the association of patient characteristics with the odds of clinical response. RESULTS: Of patients queried, 50,684 (31.5%) reported symptoms. Patients reporting DPN symptoms experienced a greater increase in new DPN diagnoses (16 percentage points; p < 0.0001) and medication use (4 percentage points; p < 0.0001) compared with those denying symptoms. Among patients reporting symptoms, women and nonwhite patients were less likely to receive a DPN diagnosis, whereas older patients were more likely to receive a DPN diagnosis. Overall, patients who were older, were Asian (hazard ratio = 0.67, 95% confidence interval = 0.63-0.77), and had lower socioeconomic status (hazard ratio = 0.89, 95% confidence interval = 0.80-0.99) were less likely to be treated. However, these racial and socioeconomic differences were not statistically significant for patients with preexisting DPN diagnoses. CONCLUSION: Patients' real-time reports of DPN symptoms were associated with increased clinical activity. Patient- and clinician-level factors associated with the likelihood of receiving a DPN diagnosis need further study because a formal diagnosis may be associated with more equitable treatment.

Antigen presentation of detergent-free glutamate decarboxylase (GAD65) is affected by human serum albumin as carrier protein.

The smaller isoform of glutamate decarboxylase (GAD65) is a major autoantigen in type 1 diabetes (TID). Its hydrophobic character requires detergent to keep the protein in solution, which complicates studies of antigen processing and presentation. In this study an attempt was made to replace detergent with human serum albumin (HSA) for in vitro antigen presentation. Different preparations of recombinant human GAD65 solubilized by HSA were incubated with Priess B cells (HLA DRB1*0401) and antigen presentation was tested with HLA DRB1*0401-restricted and epitope-specific T33.1 (GAD65 epitope 274-286) and T35 (GAD65 epitope 115-127) T-cell hybridomas. Specific epitope recognition by T33.1 (274-286) and T35 (115-127) cells varied between the different GAD65/HSA preparations, and a reverse pattern of antigen presentation was detected by the two hybridoma. The HSA-specific T-cell hybridoma 17.9 response to the different GAD65/HSA preparations followed the same pattern as that observed for the T33.1 cells. The content of immunoreactive GAD65 measured with four GAD65 antibodies indicated that the lowest GAD65 concentration resulted in the highest 274-286, but the lowest 115-127 presentation. This suggests that HSA-GAD65 interactions qualitatively affect the epitope specificity of GAD65 presentation. HSA may enhance the 274-286 epitope presentation, while suppressing the 115-127 epitope.

Validation of a Hypoglycemia Risk Stratification Tool Using Data From Continuous Glucose Monitors.

This cohort study uses data from continuous glucose monitoring to validate a hypoglycemia risk stratification tool.

Tyramine-mediated activation of sympathetic nerves inhibits insulin secretion in humans.

CONTEXT: Older studies have shown that high doses of norepinephrine infused into human subjects can inhibit insulin secretion. Similar inhibition during electrical stimulation of sympathetic nerves in animals raises the possibility that the suppression of insulin secretion seen in humans could reflect a physiological effect of sympathetic nerves on islet beta-cells. However, a direct test of the hypothesis that moderate and selective activation of these nerves is sufficient to inhibit insulin secretion in humans is lacking. OBJECTIVE: We sought to test this hypothesis by releasing moderate amounts of endogenous norepinephrine selectively from the sympathetic nerves of normal human subjects by infusing them with low doses of the indirect sympathomimetic agent tyramine. METHODS: During a single study visit, 11 healthy subjects received iv injections of arginine either alone or in combination with a low-dose tyramine infusion. Physiological (blood pressure) and biochemical (insulin, glucose, and norepinephrine) parameters were measured. RESULTS: The acute insulin response to arginine was significantly reduced during tyramine compared with that seen in the absence of tyramine (P = 0.036). CONCLUSIONS: These data suggest that moderate and selective activation of sympathetic nerves inhibits insulin release in humans.

Multiple factors affect the loss of measurable C-peptide over 6 years in newly diagnosed 15- to 35-year-old diabetic subjects.

OBJECTIVE: The aim of this study is to identify risk factors for the loss of measurable plasma C-peptide in newly diagnosed 15- to 35-year-old diabetic subjects. METHODS: This Swedish study included 778 subjects. C-peptide levels were obtained each year for 6 years after diagnosis. Loss of measurable C-peptide was defined as a level at or below the lower detection limit of the local assay (0.13 nmol/l). In addition to C-peptide, other baseline covariates included gender, age, body mass index, HLA genotype, and autoantibody levels. RESULTS: Compared with autoantibody-negative subjects, autoantibody-positive subjects had lower median baseline C-peptide (0.27 vs. 0.50, P<.001), their levels declined over the study period, and the risk of losing measurable C-peptide was significantly higher when more than one autoantibody was present [odds ratio (OR), 4.0; 95% confidence interval (CI), 2.13-7.54]. Among autoantibody-positive individuals, the presence of GAD65Ab (OR, 1.8; 95% CI, 1.24-2.51) and islet cell antibodies (OR, 1.6; 95% CI, 1.19-2.18) conferred a higher risk for loss of measurable C-peptide as did female gender (OR, 1.6; 95% CI, 1.17-2.11) and time after diagnosis (OR, 1.5 for each additional year postdiagnosis; 95% CI, 1.41-1.57). Higher baseline C-peptide levels were protective (OR, 0.5 for each additional log(e) nanomoles per liter; 95% CI, 0.36-0.58). CONCLUSIONS: This study identified autoantibody status, gender, and baseline C-peptide levels as factors that will be useful for predicting the disease course of 15- to 35-year-old diabetic individuals.

Autoantibodies in diabetes.

Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens-GAD65, IA-2, or insulin-signals an autoimmune pathogenesis of beta-cell killing. A beta-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to beta-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitope-specific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally.