Metabolic Characteristics of Recently Diagnosed Adult-Onset Autoimmune Diabetes Mellitus

Metabolic Characteristics of Recently Diagnosed Adult-Onset Autoimmune Diabetes Mellitus Abstract Context and Objective Among patients diagnosed with type 2 diabetes, autoimmune diabetes often remains undetected. Metabolic features of these patients are insufficiently characterized at present. Design, Setting, and Patients This study compared age- and sex-matched adult (aged 41 to 62 years) humans with recent-onset diabetes: patients positive for antibodies against glutamic acid decarboxylase (GAD) and/or cytoplasmic islet-cell antigen with an insulin-free period of >6 months [antibody positive/insulin negative (ab+/ins−); previously termed latent autoimmune diabetes of adults], type 1 diabetes [antibody positive/insulin positive (ab+/ins+)], and type 2 diabetes [antibody negative/insulin negative (ab−/ins−)], as well as glucose-tolerant humans (controls) of the German Diabetes Study (n = 41/group). β-Cell function was assessed from glucagon tests and intravenous glucose tolerance tests (IVGTTs), and insulin sensitivity was determined from hyperinsulinemic-euglycemic clamps. Results Of the ab+/ins− patients, 33 (81%) were initially diagnosed as having type 2 diabetes. In ab+/ins−, body mass index (BMI) was higher than in ab+/ins+ (27.8 ± 5.3 kg/m2 vs 25.0 ± 3.5 kg/m2, P < 0.05), lower than in ab−/ins− (31.9 ± 5.8 kg/m2, P < 0.05), and similar to controls (29.4 ± 6.6 kg/m2). In ab+/ins−, GAD antibody titers correlated negatively with BMI (r = −0.40, P < 0.05) and with C-peptide secretion in glucagon stimulation tests (r = −0.33, P < 0.05). β-Cell function from IVGTT was 228% higher in ab+/ins− than in ab+/ins+ but 35% lower than in ab−/ins− and 61% lower than in controls (all P < 0.05). Insulin sensitivity in ab+/ins− was comparable to ab+/ins+ and controls but 41% higher than in ab−/ins− (P < 0.05) after adjustment for BMI and fasting blood glucose or hemoglobin A1c. Conclusion Even shortly after diagnosis, ab+/ins− patients feature partly preserved β-cell function and chronic hyperglycemia, which possibly contributes to the observed impairment of whole-body insulin sensitivity. Some patients with adult-onset diabetes mellitus present with positive diabetes-associated antibodies, mainly antibodies against glutamic acid decarboxylase (GAD) and cytoplasmic islet-cell antigen (ICA) (1–3). Autoimmunity typically defines type 1 diabetes, yet there has been an attempt to identify a subgroup as latent autoimmune diabetes of the adult (LADA) (4, 5), 1.5 diabetes (6), or noninsulin-requiring autoimmune diabetes (7), based on the following criteria: positivity for diabetes-associated autoantibodies, age at diagnosis older than 30 years, and no insulin therapy during the first 6 to 12 months after diagnosis. According to current estimates, up to 10% of all patients with type 2 diabetes meet the criteria of LADA (5). These patients may present with some clinical characteristics of type 2 diabetes (8) and are preferentially treated with oral glucose-lowering medication or incretins, as insulin is not required during the first years after diagnosis (9). Of note, European guidelines do not define LADA as an independent diabetes type but classify these patients as having type 1 diabetes (10, 11). Autoantibody positivity in patients with diabetes is associated with younger age at onset, less secretion of insulin, and faster progression to insulin dependency than for antibody-negative patients (12). Of note, the metabolic phenotype might be determined by the antibody titer in that patients with a high GAD antibody titer are phenotypically closer to type 1 diabetes with lower body mass index (BMI), whereas those with a low GAD antibody titer resemble patients with type 2 diabetes (13). Regarding β-cell function in patients with LADA, some but not all studies show an accelerated decline in insulin secretion compared with type 2 diabetes (14, 15). However, only few data exist on β-cell function and insulin sensitivity in patients with adult-onset autoimmune diabetes compared with type 2 diabetes and controls. Moreover, diabetes-related comorbidities of these patients have been scarcely reported in the literature (16). Some patients appear to develop micro- and macrovascular complications despite improved glycemic control (17) and independently of features of the so-called metabolic syndrome (7). This study aimed to characterize patients with adult-onset autoimmune diabetes by differentiating between those on oral glucose-lowering medication [antibody positive/insulin negative (ab+/ins−); so-called LADA], those on insulin treatment immediately after diabetes diagnosis [antibody positive/insulin positive (ab+/ins+); type 1 diabetes], and those with type 2 diabetes (ab−/ins−). Insulin secretion and sensitivity were quantified by employing gold-standard methods (18) in patients and healthy controls of the prospective observational German Diabetes Study (GDS), which allows examining patients with short known diabetes duration of <1 year and monitoring disease progression. Subjects and methods Volunteers This nested case-control study comprised 41 ab+/ins− patients, 41 ab+/ins+ patients, 41 ab−/ins− patients, and 41 glucose-tolerant healthy humans. Of all patients tested positive for GAD antibodies and/or ICA, the ab+/ins− patients were selected by applying the following criteria: age >30 years at diagnosis and absence of insulin treatment during the first 6 months after diabetes diagnosis (19). Then, volunteers of the GDS with type 1 diabetes, those with type 2 diabetes, and healthy humans were subsequently pairwise matched for age and sex to these patients. Diabetes-related symptoms and their duration before the diagnosis, family history of diabetes, and medication as well as manifestation of diabetes-related sequelae were recorded. All participants were recruited from the GDS, which follows volunteers with recently diagnosed diabetes (known disease duration <12 months) and glucose-tolerant humans, aged 18 to 69 years. The design of the study was approved by the ethics committee of Heinrich-Heine University of Düsseldorf (reference number 4508), registered at Clinicaltrials.gov (identifier number: NCT01055093), and is performed according to the Declaration of Helsinki as reported previously (18). Briefly, diagnosis of diabetes is based on American Diabetes Assoication criteria (19). Exclusion criteria comprised the following: specific types of diabetes due to other causes; pregnancy; acute or severe chronic heart, hepatic, renal, or psychiatric diseases; and immunosuppressive treatment. Acute inflammatory syndromes were excluded by high-sensitivity C-reactive protein (hsCRP) >1 mg/dL (20) and impaired kidney function by an estimated glomerular filtration rate <60 mL/min/1.73 m2. Glucagon stimulation test The test was performed as described previously (20). Fasting blood glucose, fasting insulin, and C-peptide levels were determined. At 0 minutes, a bolus of 1 mg glucagon (GlucaGen; Novo Nordisk, Mainz, Germany) was injected intravenously, and a second blood sample was obtained after 6 minutes for measurements of insulin and C-peptide (18). The difference between C-peptide and insulin concentrations between 0 and 6 minutes was determined to assess glucagon-stimulated C-peptide and insulin secretion capacity (ΔC-peptide, Δinsulin) (21). Modified Botnia clamp test This test consists of an intravenous glucose tolerance test (IVGTT) followed by a hyperinsulinemic-euglycemic clamp test with frequent measurements of blood glucose, C-peptide, and insulin (18). The IVGTT was started by administrating a 30% glucose infusion bolus (1 mg/kg body weight) followed by timed blood sampling for 60 minutes. A priming insulin dose was then applied [10 mU ⋅ kg (body weight)−1 ⋅ min−1 for 10 minutes], continued by a constant infusion of 1.5 mU ⋅ kg (body weight)−1 ⋅ min−1 (Insuman Rapid; Sanofi, Frankfurt, Germany). Blood glucose concentration was maintained at 90 mg/dL by a variable 20% glucose infusion. The total clamp duration was 180 minutes. The mean steady-state duration (between 130 and 180 minutes) was 27 ± 1 minutes for ab+/ins−, 26 ± 1 minutes for ab−/ins−, 25 ± 1 minutes for ab+/ins+, and 26 ± 1 minutes for controls (all P > 0.05), with a mean blood glucose level during the steady state of 90 ± 1 mg/dL for patients with ab+/ins−, 91 ± 1 mg/dL for ab−/ins−, 90 ± 1 mg/dL for ab+/ins+, and 91 ± 1 mg/dL for controls (all P > 0.05). Total C-peptide secretion was determined from the incremental area under the curve for C-peptide levels during the 1-hour IVGTT, and whole-body insulin sensitivity was assessed from whole-body mean glucose infusion rates (M-value) with glucose space correction. Laboratory analyses Antibodies against GAD and ICA were measured as described (22). In brief, autoantibodies to full-length GAD and ICA were determined by a radioligand assay and by indirect immunofluorescence, respectively (23, 24). Cutoff levels were 0.9 U/mL for GAD and 5 Juvenile Diabetes Research Foundation (JDRF) units for ICA. Patients were classified as positive for antibodies against GAD or ICA with levels >0.9 U/mL for GAD or >20 JDRF units for ICA. All other parameters were analyzed as described previously (18). Statistics Data are presented as mean (standard deviation) or median (first quartile, third quartile) for continuous variables and percentages for categorical variables. Skewed data were log-transformed before analysis (M-value, total C-peptide secretion, hsCRP, triglycerides). To compare groups, covariance pattern models were applied, which account for the matched-pair design by estimating the covariance matrix of the residuals within matched pairs. Similar procedures were used to analyze binary data. To account for multiple group comparisons, the Tukey-Kramer correction was applied. Associations between parameters have been evaluated using Spearman and adjusted (partialized) Spearman correlation coefficients (r) and corresponding P values. Regression analyses adjusted for age, sex, and BMI were performed to exclude these as confounding factors. Additional analyses were adjusted for fasting blood glucose and hemoglobin A1c (HbA1c). P values <5% were considered to indicate significant differences or correlations. Statistical analyses were performed with SAS (version 9.3; SAS Institute, Cary, NC). Results Anthropometric and clinical characteristics of the study population Anthropometric and clinical data are shown in Table 1. Patients with ab+/ins+ were slightly younger than participants of the other groups. BMI was on average 10% higher in ab+/ins− patients than in ab+/ins+ patients, 22% lower than in ab−/ins− patients, and intermediary in controls. The prevalence of a family history of diabetes was similar between all groups of patients with diabetes. hsCRP and HbA1c did not differ between the diabetes groups but were lower in the control group (all P < 0.05). Most patients with diabetes had excellent glycemic control with HbA1c <7% (53 mmol/mol) according to current guidelines (11) [30 (73%) of ab+/ins−, 30 (73%) of ab+/ins+, and 33 (81%) of ab−/ins− patients]. Table 1. Characteristics of the Study Population Characteristic  ab+/ins−  ab+/ins+  ab−/ins−  Controls  Total No. (male/female)  41 (25/16)  41 (25/16)  41 (25/16)  41 (25/16)  Age, y  50.8 ± 9.4a  48.0 ± 7.0b,c,d  50.8 ± 9.3a  51.1 ± 9.7a  BMI, kg/m2  27.8 ± 5.3a,b  25.0 ± 3.5b,c,d  31.9 ± 5.8a,d  29.4 ± 6.6a  WHR  0.93 ± 0.09  0.90 ± 0.10  0.96 ± 0.07c  0.92 ± 0.08b  Known diabetes duration, mo  6.9 ± 3.4  6.1 ± 2.6  5.9 ± 3.1  —  Duration of diabetes-related symptoms prior to diagnosis, mo  3.6 ± 4.7  2.4 ± 4.2  4.0 ± 5.6  —  Family history of type 1 diabetes, n (%)  2 (5)  1 (2)  1 (2)  —  Family history of type 2 diabetes, n (%)  12 (29)  12 (29)  21 (51)  —  hsCRP, mg/dL  0.18 (0.09, 0.34)c  0.13 (0.05, 0.22)c  0.37 (0.18, 0.57)c  0.13 (0.07, 0.23)a,b,d  HbA1c, % (mmol/mol)  6.6 ± 1.1 (49 ± 12)c  7.0 ± 1.5 (52 ± 16)c  6.3 ± 0.7 (45 ± 8)c  5.3 ± 0.3 (34 ± 3)a,b,d  eGFR, mL/min/1.73 m2  91.3 ± 14.9  89.5 ± 12.4  85.4 ± 14.8  91.8 ± 13.1  Total cholesterol, mg/dL  193.0 ± 33.2a  206.7 ± 40.7d  202.0 ± 53.3  204.5 ± 32.2  LDL cholesterol, mg/dL  120.3 ± 34.0a  127.0 ± 39.3d  125.3 ± 36.5  134.3 ± 33.6  HDL cholesterol, mg/dL  53.0 ± 16.7a,c  63.7 ± 19.7b,d  45.3 ± 12.9a  60.3 ± 16.5d  Triglycerides, mg/dL  128.3 ± 89.7  92.4 ± 49.5  146.3 ± 77.4c  110.3 ± 52.8b  Lipid-lowering therapy, n (%)  4 (10)  1 (2)  6 (15)  0 (0)  Antihypertensive therapy, n (%)  16 (39)  5 (12)b  20 (49)a,c  11 (27)b  GAD, U/mL  2.2 (0.9, 34.0)a  38.9 (12.6, 92.4)d  0.1 (0.1, 0.2)  0.1 (0.1, 0.2)  ICA >20 JDRF, n (%)  30 (73)  41 (100)  0 (0)  0 (0)  Characteristic  ab+/ins−  ab+/ins+  ab−/ins−  Controls  Total No. (male/female)  41 (25/16)  41 (25/16)  41 (25/16)  41 (25/16)  Age, y  50.8 ± 9.4a  48.0 ± 7.0b,c,d  50.8 ± 9.3a  51.1 ± 9.7a  BMI, kg/m2  27.8 ± 5.3a,b  25.0 ± 3.5b,c,d  31.9 ± 5.8a,d  29.4 ± 6.6a  WHR  0.93 ± 0.09  0.90 ± 0.10  0.96 ± 0.07c  0.92 ± 0.08b  Known diabetes duration, mo  6.9 ± 3.4  6.1 ± 2.6  5.9 ± 3.1  —  Duration of diabetes-related symptoms prior to diagnosis, mo  3.6 ± 4.7  2.4 ± 4.2  4.0 ± 5.6  —  Family history of type 1 diabetes, n (%)  2 (5)  1 (2)  1 (2)  —  Family history of type 2 diabetes, n (%)  12 (29)  12 (29)  21 (51)  —  hsCRP, mg/dL  0.18 (0.09, 0.34)c  0.13 (0.05, 0.22)c  0.37 (0.18, 0.57)c  0.13 (0.07, 0.23)a,b,d  HbA1c, % (mmol/mol)  6.6 ± 1.1 (49 ± 12)c  7.0 ± 1.5 (52 ± 16)c  6.3 ± 0.7 (45 ± 8)c  5.3 ± 0.3 (34 ± 3)a,b,d  eGFR, mL/min/1.73 m2  91.3 ± 14.9  89.5 ± 12.4  85.4 ± 14.8  91.8 ± 13.1  Total cholesterol, mg/dL  193.0 ± 33.2a  206.7 ± 40.7d  202.0 ± 53.3  204.5 ± 32.2  LDL cholesterol, mg/dL  120.3 ± 34.0a  127.0 ± 39.3d  125.3 ± 36.5  134.3 ± 33.6  HDL cholesterol, mg/dL  53.0 ± 16.7a,c  63.7 ± 19.7b,d  45.3 ± 12.9a  60.3 ± 16.5d  Triglycerides, mg/dL  128.3 ± 89.7  92.4 ± 49.5  146.3 ± 77.4c  110.3 ± 52.8b  Lipid-lowering therapy, n (%)  4 (10)  1 (2)  6 (15)  0 (0)  Antihypertensive therapy, n (%)  16 (39)  5 (12)b  20 (49)a,c  11 (27)b  GAD, U/mL  2.2 (0.9, 34.0)a  38.9 (12.6, 92.4)d  0.1 (0.1, 0.2)  0.1 (0.1, 0.2)  ICA >20 JDRF, n (%)  30 (73)  41 (100)  0 (0)  0 (0)  Anthropometric and clinical data of the study population are shown as n (%), mean ± standard deviation, or median (first quartile, third quartile). Positive GAD antibodies and/or cytoplasmic ICAs were used as markers for diagnosing autoimmune diabetes (ab+). Abbreviations: eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; WHR, waist-to-hip ratio. a P ≤ 0.05 vs type 1 diabetes. b P ≤ 0.05 vs type 2 diabetes. c P ≤ 0.05 vs controls. d P ≤ 0.05 vs LADA. View Large Per definition, only patients with LADA and type 1 diabetes had positive diabetes-associated autoantibodies (ab+). Compared with ab+/ins+ patients, ab+/ins− patients had 95% lower GAD titers [2.2 (0.9, 34.0) U/mL vs 38.9 (12.6, 92.4) U/mL, P < 0.05]. ICA titers >20 JDRF units were found in 30 (73%) ab+/ins− and in 41 (100%) ab+/ins+ patients. BMI negatively correlated with GAD titers in ab+/ins− patients (r = −0.47, P < 0.05). Metabolic syndrome components and diabetes-related comorbidities When analyzing further cardiovascular risk factors comprising the so-called metabolic syndrome (25), we observed that there was no difference in waist-to-hip ratio between ab+/ins− patients and patients of the other groups. The lipid profile as presented in Table 1 shows similarities in total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol and triglyceride levels between ab+/ins− and ab−/ins−. Of the ab+/ins− patients, 29 (71%) had fasting triglyceride levels <150 mg/dL (26), and 14 (34%) achieved LDL levels <100 mg/dL as recommended in the European Society of Cardiology guidelines (11). Hypertension was present in 22 (54%) of the patients with ab+/ins−, 14 (34%) of the patients with ab+/ins+, 29 (71%) of the patients with ab−/ins−, and 21 (51%) of the controls. No differences were evident between ab+/ins− patients and patients of the other groups with regard to antihypertensive treatment. Regarding diabetes-related comorbidities, some patients had micro- and macrovascular complications already within the first year after diagnosis: two cases of diabetic retinopathy, one case of diabetic neuropathy, and two cases of myocardial infarction in patients with ab+/ins− (12%); one case of peripheral artery disease and one case of stroke in patients with ab−/ins− (5%); one case of peripheral artery disease in glucose-tolerant controls (2%); and no diagnosed complications in patients with ab+/ins+ (0%). Insulin sensitivity and β-cell function Whole-body insulin sensitivity in ab+/ins− patients was comparable to that of ab+/ins+ patients but 41% higher than in ab−/ins− patients and 16% lower than in controls (Fig. 1A). After further adjustments for fasting blood glucose and HbA1c, only differences between ab+/ins− patients and ab−/ins− patients remained (P < 0.05). Figure 1. View largeDownload slide Metabolic characteristics of patients with newly diagnosed LADA (ab+/ins−), patients with type 1 diabetes (ab+/ins+), patients with type 2 diabetes (ab−/ins−), and controls (con) showing (A) insulin sensitivity (M-value), (B) total C-peptide secretion during IVGTT, and (C) C-peptide and (D) insulin secretion after glucagon stimulation. Box plots show medians and whiskers from minimum to maximum. P values refer to comparison of data adjusted for age, sex, and BMI. Data were ln-transformed where applicable. *P ≤ 0.05, **P ≤ 0.05 after correction for multiple testing. Figure 1. View largeDownload slide Metabolic characteristics of patients with newly diagnosed LADA (ab+/ins−), patients with type 1 diabetes (ab+/ins+), patients with type 2 diabetes (ab−/ins−), and controls (con) showing (A) insulin sensitivity (M-value), (B) total C-peptide secretion during IVGTT, and (C) C-peptide and (D) insulin secretion after glucagon stimulation. Box plots show medians and whiskers from minimum to maximum. P values refer to comparison of data adjusted for age, sex, and BMI. Data were ln-transformed where applicable. *P ≤ 0.05, **P ≤ 0.05 after correction for multiple testing. With regard to β-cell function, total C-peptide secretion during IVGTT (Fig. 1B) was 228% higher in ab+/ins− patients compared with ab+/ins+ patients, 35% lower compared with ab−/ins− patients, and 61% lower compared with controls (all P < 0.05). These differences remained after adjustment for age, sex, and BMI. Similarly, ΔC-peptide levels following glucagon stimulation (Fig. 1C) were 180% higher in ab+/ins− patients compared with ab+/ins+ patients, 31% lower than in ab−/ins− patients, and 53% lower than in controls (all P < 0.05). Furthermore, in patients with ab+/ins−, GAD antibody titers inversely correlated with ΔC-peptide (r = −0.33, P < 0.05) (Fig. 2). Correspondingly, Δinsulin in ab+/ins− patients was 144% higher compared with ab+/ins+ patients, 62% lower than in ab−/ins− patients, and 138% lower than in controls (all P < 0.05) (Fig. 1D). Further analyses with adjustments for fasting glucose confirmed higher insulin secretory response in ab+/ins− compared with ab+/ins+ and controls and similarity between ab+/ins− and ab−/ins−. Figure 2. View largeDownload slide Correlation of GAD antibodies with BMI (A, B), with β-cell function expressed as total C-peptide secretion during the IVGTT (C, D), and with C-peptide secretion upon glucagon stimulation (E, F) in ab+/ins− patients (circles) and ab+/ins+ patients (triangles). (A, E) BMI and glucagon-stimulated C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins− patients. (D) Glucose-stimulated total C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins+ patients. Individual data are presented as scatter plots with linear regression including 95% confidence intervals and with partial Pearson correlations coefficients (r) and corresponding P values. Figure 2. View largeDownload slide Correlation of GAD antibodies with BMI (A, B), with β-cell function expressed as total C-peptide secretion during the IVGTT (C, D), and with C-peptide secretion upon glucagon stimulation (E, F) in ab+/ins− patients (circles) and ab+/ins+ patients (triangles). (A, E) BMI and glucagon-stimulated C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins− patients. (D) Glucose-stimulated total C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins+ patients. Individual data are presented as scatter plots with linear regression including 95% confidence intervals and with partial Pearson correlations coefficients (r) and corresponding P values. Discussion The ab+/ins− patients, reflecting the so-called LADA, as defined by positive diabetes-associated antibodies, age >30 years at diagnosis, and no insulin treatment during the first 6 months upon diabetes diagnosis, had higher insulin sensitivity than matched patients with type 2 diabetes and presented with better β-cell function parameters than patients with type 1 diabetes, independent of BMI. In the ab+/ins− patients, GAD antibody titers were found to inversely correlate with both C-peptide release after glucagon stimulation and BMI. Of note, the high prevalence of diabetes-related complications is noteworthy, despite the lower prevalence of components of the metabolic syndrome in these newly diagnosed ab+/ins− patients (27). Although ab+/ins− patients have a lower body weight and younger age at onset of diabetes than patients with type 2 diabetes (28), previous studies have attributed differences in metabolic parameters to BMI (14). Consequently, we adjusted our analyses to account for this confounding factor. Also, similar to the study by Hawa et al. (28), we found an inverse association between BMI and the GAD autoantibody titer, indicating that ab+/ins− patients with lower β-cell–directed immunoreactivity are closer to the typical phenotype of type 2 diabetes. Previous studies revealed contradictory data on the relationship between BMI and GAD autoantibodies, either in favor (29) or against (30) a role of obesity as an accelerator of insulin resistance, thereby driving the immune response and promoting β-cell apoptosis. Although the cross-sectional design does not allow us to establish causality, the current study detected an interaction between BMI, GAD autoantibody titers, and β-cell function. Adjusting for ΔC-peptide abolished the correlation between BMI and GAD autoantibodies, suggesting that this correlation is mediated by impaired β-cell function. In line, a direct relationship between BMI and ΔC-peptide has been reported (31). Because of its prospective design (18), the source study of this analysis, the GDS, should be able to address at least some aspects of the role of obesity for diabetes-related autoimmunity and β-cell function in the future. Previous studies implied that the onset of disease in patients with adult-onset autoimmune diabetes can be insidious, similar to that observed in patients with type 2 diabetes, which promotes a postponed medical attendance and possibly a delayed initiation of adequate treatment (5). Nevertheless, we showed that latency of diagnosis following the first appearance of diabetes-related symptoms was not different between ab+/ins− and ab−/ins− patients, and neither were family history of diabetes nor HbA1c levels. Therefore, the clinical appearance does not show clear criteria to distinguish latent autoimmune diabetes from type 2 diabetes. The methods of achieving glycemic control have been viewed with controversy in ab+/ins− patients because there is no consensus on therapeutic strategies (32). Previous studies have reported insufficient glycemic control in ab+/ins− patients, endorsing immediate insulin treatment (9). In contrast, in our cohort, HbA1c levels in ab+/ins− patients were comparable to those of ab−/ins− patients and well within the guideline-imposed limits for glycemic control (11). Furthermore, there was no difference in those patients incorrectly attributed to type 2 diabetes compared with those attributed to so-called LADA. Although guidelines (11) advocate for distinguishing patients presenting with diabetes-associated antibodies from type 2 diabetes, in our cohort, most ab+/ins− patients were initially diagnosed as having type 2 diabetes. Even without insulin treatment 6 months from disease onset, 73% of the ab+/ins− patients achieve excellent glycemic control when treated with biguanides, sulphonylureas, and/or dipeptidylpeptidase-4 inhibitor (10, 33). Previous studies on ab+/ins− patients have described pronounced dyslipidemia (34), which is regarded as an important atherogenic risk factor. This, coupled with reduced insulin sensitivity and hypertension, can contribute to an increased cardiovascular risk (35), increasing the hazard for vascular events. Our findings are in line with a Spanish study, which showed only satisfactory lipid control in ab+/ins− patients even after several years of disease duration (36). Similarly, ab+/ins− patients of our study had a heterogeneous lipid profile, with lower LDL levels than ab+/ins+ patients independent of age, BMI, and waist-to-hip ratio, and presumably benefited from the lipid-lowering therapy but at the same time had lower high-density lipoprotein levels than patients with type 2 diabetes. Our results warrant further research into the factors influencing the lipid profile of ab+/ins− patients, as we showed the presence of micro- and macrovascular complications in 12% of these patients already within the first year after diagnosis. However, this study was not powered to compare the prevalence of diabetes-related complications between the groups. Up to now, ab+/ins− patients have been scarcely investigated with regard to insulin sensitivity. There is compelling evidence that insulin resistance can be present in both type 2 diabetes and type 1 diabetes (37), although to a lesser degree in the latter. Our results suggest that a higher BMI is not the main contender in determining insulin resistance in adult-onset autoimmune diabetes. Even though ab+/ins− patients had higher whole-body insulin sensitivity than their type 2 diabetes counterparts of similar age, they also had a lower insulin sensitivity than age- and BMI-matched controls. The effect of elevated fasting glucose and glycemic control on the group comparison analyses indicates that hyperglycemia may at least contribute to the reduced insulin sensitivity in ab+ patients. Given the short known disease duration of these patients, these findings suggest an important role of glucose toxicity even in the early course of disease. There are contradicting data on describing LADA as a distinct disease entity with a unique metabolism, as it encompasses features that are present in both type 1 and type 2 diabetes. Interestingly, our ab+/ins− patients showed both better insulin sensitivity and preserved β-cell function, distinct from patients with type 2 diabetes, independent of age, sex, or BMI. The preserved residual capacity of C-peptide stimulation in ab+/ins− patients reflects a decelerated loss of β-cell functionality compared with type 1 diabetes. Nonetheless, patients with autoimmune diabetes who have a reduced C-peptide secretion will be prone to a shorter interval of insulin-free therapy than patients with type 2 diabetes (38). Despite the presence of β-cell-directed autoimmunity, confirmed by the presence of diabetes-associated autoantibodies, there seems to be only a mild autoimmune reactivity. The differences between ab+/ins− patients and controls were preserved after adjustments for fasting blood glucose with correction for multiple analysis, thereby ruling out a relevant role of the fasting blood glucose level as a confounding factor for β-cell function. The strength of our study design relies on the well-characterized metabolism of ab+/ins− patients in comparison with matched patients with type 1 and type 2 diabetes and healthy controls. Patients included in the study had similar disease duration and had undergone gold-standard methods following standard operating procedures to evaluate β-cell function and insulin sensitivity. The specific metabolic features of ab+/ins− patients should raise clinical awareness. These patients will not benefit from insulin substitution based on established dosing algorithms for type 1 diabetes but will require more individualized treatment, taking into account their lower insulin sensitivity. Furthermore, in the presence of diabetes-related autoimmunity, patients may also need intensive lifestyle modification and monitoring of both physical fitness and body fat mass to improve their insulin resistance. Although the 8.3% prevalence of ab+/ins− in patients with type 2 diabetes of the GDC cohort lies in the range of previously described studies, the relatively small number of subjects is a limitation of the study. In conclusion, adult patients with recently diagnosed autoimmune diabetes have higher insulin sensitivity than patients with type 2 diabetes, but specifically, patients with autoimmune diabetes without initial insulin treatment (previously termed LADA) have a partly preserved β-cell function at the onset of diabetes. Compared with healthy humans, these ab+/ins− patients show impaired whole-body insulin sensitivity possibly due to chronic hyperglycemia. Abbreviations: ab−/ins− antibody negative/insulin negative ab+/ins− antibody positive/insulin negative ab+/ins+ antibody positive/insulin positive BMI body mass index GAD glutamic acid decarboxylase GDS German Diabetes Study HbA1c hemoglobin A1c hsCRP high-sensitivity C-reactive protein ICA islet-cell antigen IVGTT intravenous glucose tolerance test JDRF Juvenile Diabetes Research Foundation LADA latent autoimmune diabetes of the adult LDL low-density lipoprotein. Acknowledgments Financial Support: The GDS was initiated and financed by the DDZ–German Diabetes Center, which is funded by the German Federal Ministry of Health (Berlin, Germany) and the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany) and from the German Federal Ministry of Education and Research (BMBF) grant to the German Center for Diabetes Research (DZD e.V.) and the Schmutzler Stiftung, Germany. Clinical Trial Information: ClinicalTrials.gov no. NCT01055093 (registered 25 January 2010). Author Contributions: O.P.Z. wrote the manuscript and researched data. K.B., Y.K., D.F.M., and M.S. researched data. P.B. and K.S. performed the statistical analyses. J.S., K.M., V.B., N.C.S., and M.R. researched data, contributed to the discussion, and reviewed/edited the manuscript. All authors critically reviewed the manuscript. M.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript. Disclosure Summary: N.C.S. is employed by Lilly Deutschland GmbH and a visiting scientist at the Institute for Clinical Diabetology of the German Diabetes Center. The other authors have nothing to disclose. References 1. Stenström G, Gottsäter A, Bakhtadze E, Berger B, Sundkvist G. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. 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Insulin resistance in type 1 diabetes mellitus. Metabolism . 2015; 64( 12): 1629– 1639. Google Scholar CrossRef Search ADS PubMed  38. Nambam B, Aggarwal S, Jain A. Latent autoimmune diabetes in adults: a distinct but heterogeneous clinical entity. World J Diabetes . 2010; 1( 4): 111– 115. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

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Endocrine Society
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Copyright © 2018 Endocrine Society
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Abstract

Abstract Context and Objective Among patients diagnosed with type 2 diabetes, autoimmune diabetes often remains undetected. Metabolic features of these patients are insufficiently characterized at present. Design, Setting, and Patients This study compared age- and sex-matched adult (aged 41 to 62 years) humans with recent-onset diabetes: patients positive for antibodies against glutamic acid decarboxylase (GAD) and/or cytoplasmic islet-cell antigen with an insulin-free period of >6 months [antibody positive/insulin negative (ab+/ins−); previously termed latent autoimmune diabetes of adults], type 1 diabetes [antibody positive/insulin positive (ab+/ins+)], and type 2 diabetes [antibody negative/insulin negative (ab−/ins−)], as well as glucose-tolerant humans (controls) of the German Diabetes Study (n = 41/group). β-Cell function was assessed from glucagon tests and intravenous glucose tolerance tests (IVGTTs), and insulin sensitivity was determined from hyperinsulinemic-euglycemic clamps. Results Of the ab+/ins− patients, 33 (81%) were initially diagnosed as having type 2 diabetes. In ab+/ins−, body mass index (BMI) was higher than in ab+/ins+ (27.8 ± 5.3 kg/m2 vs 25.0 ± 3.5 kg/m2, P < 0.05), lower than in ab−/ins− (31.9 ± 5.8 kg/m2, P < 0.05), and similar to controls (29.4 ± 6.6 kg/m2). In ab+/ins−, GAD antibody titers correlated negatively with BMI (r = −0.40, P < 0.05) and with C-peptide secretion in glucagon stimulation tests (r = −0.33, P < 0.05). β-Cell function from IVGTT was 228% higher in ab+/ins− than in ab+/ins+ but 35% lower than in ab−/ins− and 61% lower than in controls (all P < 0.05). Insulin sensitivity in ab+/ins− was comparable to ab+/ins+ and controls but 41% higher than in ab−/ins− (P < 0.05) after adjustment for BMI and fasting blood glucose or hemoglobin A1c. Conclusion Even shortly after diagnosis, ab+/ins− patients feature partly preserved β-cell function and chronic hyperglycemia, which possibly contributes to the observed impairment of whole-body insulin sensitivity. Some patients with adult-onset diabetes mellitus present with positive diabetes-associated antibodies, mainly antibodies against glutamic acid decarboxylase (GAD) and cytoplasmic islet-cell antigen (ICA) (1–3). Autoimmunity typically defines type 1 diabetes, yet there has been an attempt to identify a subgroup as latent autoimmune diabetes of the adult (LADA) (4, 5), 1.5 diabetes (6), or noninsulin-requiring autoimmune diabetes (7), based on the following criteria: positivity for diabetes-associated autoantibodies, age at diagnosis older than 30 years, and no insulin therapy during the first 6 to 12 months after diagnosis. According to current estimates, up to 10% of all patients with type 2 diabetes meet the criteria of LADA (5). These patients may present with some clinical characteristics of type 2 diabetes (8) and are preferentially treated with oral glucose-lowering medication or incretins, as insulin is not required during the first years after diagnosis (9). Of note, European guidelines do not define LADA as an independent diabetes type but classify these patients as having type 1 diabetes (10, 11). Autoantibody positivity in patients with diabetes is associated with younger age at onset, less secretion of insulin, and faster progression to insulin dependency than for antibody-negative patients (12). Of note, the metabolic phenotype might be determined by the antibody titer in that patients with a high GAD antibody titer are phenotypically closer to type 1 diabetes with lower body mass index (BMI), whereas those with a low GAD antibody titer resemble patients with type 2 diabetes (13). Regarding β-cell function in patients with LADA, some but not all studies show an accelerated decline in insulin secretion compared with type 2 diabetes (14, 15). However, only few data exist on β-cell function and insulin sensitivity in patients with adult-onset autoimmune diabetes compared with type 2 diabetes and controls. Moreover, diabetes-related comorbidities of these patients have been scarcely reported in the literature (16). Some patients appear to develop micro- and macrovascular complications despite improved glycemic control (17) and independently of features of the so-called metabolic syndrome (7). This study aimed to characterize patients with adult-onset autoimmune diabetes by differentiating between those on oral glucose-lowering medication [antibody positive/insulin negative (ab+/ins−); so-called LADA], those on insulin treatment immediately after diabetes diagnosis [antibody positive/insulin positive (ab+/ins+); type 1 diabetes], and those with type 2 diabetes (ab−/ins−). Insulin secretion and sensitivity were quantified by employing gold-standard methods (18) in patients and healthy controls of the prospective observational German Diabetes Study (GDS), which allows examining patients with short known diabetes duration of <1 year and monitoring disease progression. Subjects and methods Volunteers This nested case-control study comprised 41 ab+/ins− patients, 41 ab+/ins+ patients, 41 ab−/ins− patients, and 41 glucose-tolerant healthy humans. Of all patients tested positive for GAD antibodies and/or ICA, the ab+/ins− patients were selected by applying the following criteria: age >30 years at diagnosis and absence of insulin treatment during the first 6 months after diabetes diagnosis (19). Then, volunteers of the GDS with type 1 diabetes, those with type 2 diabetes, and healthy humans were subsequently pairwise matched for age and sex to these patients. Diabetes-related symptoms and their duration before the diagnosis, family history of diabetes, and medication as well as manifestation of diabetes-related sequelae were recorded. All participants were recruited from the GDS, which follows volunteers with recently diagnosed diabetes (known disease duration <12 months) and glucose-tolerant humans, aged 18 to 69 years. The design of the study was approved by the ethics committee of Heinrich-Heine University of Düsseldorf (reference number 4508), registered at Clinicaltrials.gov (identifier number: NCT01055093), and is performed according to the Declaration of Helsinki as reported previously (18). Briefly, diagnosis of diabetes is based on American Diabetes Assoication criteria (19). Exclusion criteria comprised the following: specific types of diabetes due to other causes; pregnancy; acute or severe chronic heart, hepatic, renal, or psychiatric diseases; and immunosuppressive treatment. Acute inflammatory syndromes were excluded by high-sensitivity C-reactive protein (hsCRP) >1 mg/dL (20) and impaired kidney function by an estimated glomerular filtration rate <60 mL/min/1.73 m2. Glucagon stimulation test The test was performed as described previously (20). Fasting blood glucose, fasting insulin, and C-peptide levels were determined. At 0 minutes, a bolus of 1 mg glucagon (GlucaGen; Novo Nordisk, Mainz, Germany) was injected intravenously, and a second blood sample was obtained after 6 minutes for measurements of insulin and C-peptide (18). The difference between C-peptide and insulin concentrations between 0 and 6 minutes was determined to assess glucagon-stimulated C-peptide and insulin secretion capacity (ΔC-peptide, Δinsulin) (21). Modified Botnia clamp test This test consists of an intravenous glucose tolerance test (IVGTT) followed by a hyperinsulinemic-euglycemic clamp test with frequent measurements of blood glucose, C-peptide, and insulin (18). The IVGTT was started by administrating a 30% glucose infusion bolus (1 mg/kg body weight) followed by timed blood sampling for 60 minutes. A priming insulin dose was then applied [10 mU ⋅ kg (body weight)−1 ⋅ min−1 for 10 minutes], continued by a constant infusion of 1.5 mU ⋅ kg (body weight)−1 ⋅ min−1 (Insuman Rapid; Sanofi, Frankfurt, Germany). Blood glucose concentration was maintained at 90 mg/dL by a variable 20% glucose infusion. The total clamp duration was 180 minutes. The mean steady-state duration (between 130 and 180 minutes) was 27 ± 1 minutes for ab+/ins−, 26 ± 1 minutes for ab−/ins−, 25 ± 1 minutes for ab+/ins+, and 26 ± 1 minutes for controls (all P > 0.05), with a mean blood glucose level during the steady state of 90 ± 1 mg/dL for patients with ab+/ins−, 91 ± 1 mg/dL for ab−/ins−, 90 ± 1 mg/dL for ab+/ins+, and 91 ± 1 mg/dL for controls (all P > 0.05). Total C-peptide secretion was determined from the incremental area under the curve for C-peptide levels during the 1-hour IVGTT, and whole-body insulin sensitivity was assessed from whole-body mean glucose infusion rates (M-value) with glucose space correction. Laboratory analyses Antibodies against GAD and ICA were measured as described (22). In brief, autoantibodies to full-length GAD and ICA were determined by a radioligand assay and by indirect immunofluorescence, respectively (23, 24). Cutoff levels were 0.9 U/mL for GAD and 5 Juvenile Diabetes Research Foundation (JDRF) units for ICA. Patients were classified as positive for antibodies against GAD or ICA with levels >0.9 U/mL for GAD or >20 JDRF units for ICA. All other parameters were analyzed as described previously (18). Statistics Data are presented as mean (standard deviation) or median (first quartile, third quartile) for continuous variables and percentages for categorical variables. Skewed data were log-transformed before analysis (M-value, total C-peptide secretion, hsCRP, triglycerides). To compare groups, covariance pattern models were applied, which account for the matched-pair design by estimating the covariance matrix of the residuals within matched pairs. Similar procedures were used to analyze binary data. To account for multiple group comparisons, the Tukey-Kramer correction was applied. Associations between parameters have been evaluated using Spearman and adjusted (partialized) Spearman correlation coefficients (r) and corresponding P values. Regression analyses adjusted for age, sex, and BMI were performed to exclude these as confounding factors. Additional analyses were adjusted for fasting blood glucose and hemoglobin A1c (HbA1c). P values <5% were considered to indicate significant differences or correlations. Statistical analyses were performed with SAS (version 9.3; SAS Institute, Cary, NC). Results Anthropometric and clinical characteristics of the study population Anthropometric and clinical data are shown in Table 1. Patients with ab+/ins+ were slightly younger than participants of the other groups. BMI was on average 10% higher in ab+/ins− patients than in ab+/ins+ patients, 22% lower than in ab−/ins− patients, and intermediary in controls. The prevalence of a family history of diabetes was similar between all groups of patients with diabetes. hsCRP and HbA1c did not differ between the diabetes groups but were lower in the control group (all P < 0.05). Most patients with diabetes had excellent glycemic control with HbA1c <7% (53 mmol/mol) according to current guidelines (11) [30 (73%) of ab+/ins−, 30 (73%) of ab+/ins+, and 33 (81%) of ab−/ins− patients]. Table 1. Characteristics of the Study Population Characteristic  ab+/ins−  ab+/ins+  ab−/ins−  Controls  Total No. (male/female)  41 (25/16)  41 (25/16)  41 (25/16)  41 (25/16)  Age, y  50.8 ± 9.4a  48.0 ± 7.0b,c,d  50.8 ± 9.3a  51.1 ± 9.7a  BMI, kg/m2  27.8 ± 5.3a,b  25.0 ± 3.5b,c,d  31.9 ± 5.8a,d  29.4 ± 6.6a  WHR  0.93 ± 0.09  0.90 ± 0.10  0.96 ± 0.07c  0.92 ± 0.08b  Known diabetes duration, mo  6.9 ± 3.4  6.1 ± 2.6  5.9 ± 3.1  —  Duration of diabetes-related symptoms prior to diagnosis, mo  3.6 ± 4.7  2.4 ± 4.2  4.0 ± 5.6  —  Family history of type 1 diabetes, n (%)  2 (5)  1 (2)  1 (2)  —  Family history of type 2 diabetes, n (%)  12 (29)  12 (29)  21 (51)  —  hsCRP, mg/dL  0.18 (0.09, 0.34)c  0.13 (0.05, 0.22)c  0.37 (0.18, 0.57)c  0.13 (0.07, 0.23)a,b,d  HbA1c, % (mmol/mol)  6.6 ± 1.1 (49 ± 12)c  7.0 ± 1.5 (52 ± 16)c  6.3 ± 0.7 (45 ± 8)c  5.3 ± 0.3 (34 ± 3)a,b,d  eGFR, mL/min/1.73 m2  91.3 ± 14.9  89.5 ± 12.4  85.4 ± 14.8  91.8 ± 13.1  Total cholesterol, mg/dL  193.0 ± 33.2a  206.7 ± 40.7d  202.0 ± 53.3  204.5 ± 32.2  LDL cholesterol, mg/dL  120.3 ± 34.0a  127.0 ± 39.3d  125.3 ± 36.5  134.3 ± 33.6  HDL cholesterol, mg/dL  53.0 ± 16.7a,c  63.7 ± 19.7b,d  45.3 ± 12.9a  60.3 ± 16.5d  Triglycerides, mg/dL  128.3 ± 89.7  92.4 ± 49.5  146.3 ± 77.4c  110.3 ± 52.8b  Lipid-lowering therapy, n (%)  4 (10)  1 (2)  6 (15)  0 (0)  Antihypertensive therapy, n (%)  16 (39)  5 (12)b  20 (49)a,c  11 (27)b  GAD, U/mL  2.2 (0.9, 34.0)a  38.9 (12.6, 92.4)d  0.1 (0.1, 0.2)  0.1 (0.1, 0.2)  ICA >20 JDRF, n (%)  30 (73)  41 (100)  0 (0)  0 (0)  Characteristic  ab+/ins−  ab+/ins+  ab−/ins−  Controls  Total No. (male/female)  41 (25/16)  41 (25/16)  41 (25/16)  41 (25/16)  Age, y  50.8 ± 9.4a  48.0 ± 7.0b,c,d  50.8 ± 9.3a  51.1 ± 9.7a  BMI, kg/m2  27.8 ± 5.3a,b  25.0 ± 3.5b,c,d  31.9 ± 5.8a,d  29.4 ± 6.6a  WHR  0.93 ± 0.09  0.90 ± 0.10  0.96 ± 0.07c  0.92 ± 0.08b  Known diabetes duration, mo  6.9 ± 3.4  6.1 ± 2.6  5.9 ± 3.1  —  Duration of diabetes-related symptoms prior to diagnosis, mo  3.6 ± 4.7  2.4 ± 4.2  4.0 ± 5.6  —  Family history of type 1 diabetes, n (%)  2 (5)  1 (2)  1 (2)  —  Family history of type 2 diabetes, n (%)  12 (29)  12 (29)  21 (51)  —  hsCRP, mg/dL  0.18 (0.09, 0.34)c  0.13 (0.05, 0.22)c  0.37 (0.18, 0.57)c  0.13 (0.07, 0.23)a,b,d  HbA1c, % (mmol/mol)  6.6 ± 1.1 (49 ± 12)c  7.0 ± 1.5 (52 ± 16)c  6.3 ± 0.7 (45 ± 8)c  5.3 ± 0.3 (34 ± 3)a,b,d  eGFR, mL/min/1.73 m2  91.3 ± 14.9  89.5 ± 12.4  85.4 ± 14.8  91.8 ± 13.1  Total cholesterol, mg/dL  193.0 ± 33.2a  206.7 ± 40.7d  202.0 ± 53.3  204.5 ± 32.2  LDL cholesterol, mg/dL  120.3 ± 34.0a  127.0 ± 39.3d  125.3 ± 36.5  134.3 ± 33.6  HDL cholesterol, mg/dL  53.0 ± 16.7a,c  63.7 ± 19.7b,d  45.3 ± 12.9a  60.3 ± 16.5d  Triglycerides, mg/dL  128.3 ± 89.7  92.4 ± 49.5  146.3 ± 77.4c  110.3 ± 52.8b  Lipid-lowering therapy, n (%)  4 (10)  1 (2)  6 (15)  0 (0)  Antihypertensive therapy, n (%)  16 (39)  5 (12)b  20 (49)a,c  11 (27)b  GAD, U/mL  2.2 (0.9, 34.0)a  38.9 (12.6, 92.4)d  0.1 (0.1, 0.2)  0.1 (0.1, 0.2)  ICA >20 JDRF, n (%)  30 (73)  41 (100)  0 (0)  0 (0)  Anthropometric and clinical data of the study population are shown as n (%), mean ± standard deviation, or median (first quartile, third quartile). Positive GAD antibodies and/or cytoplasmic ICAs were used as markers for diagnosing autoimmune diabetes (ab+). Abbreviations: eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; WHR, waist-to-hip ratio. a P ≤ 0.05 vs type 1 diabetes. b P ≤ 0.05 vs type 2 diabetes. c P ≤ 0.05 vs controls. d P ≤ 0.05 vs LADA. View Large Per definition, only patients with LADA and type 1 diabetes had positive diabetes-associated autoantibodies (ab+). Compared with ab+/ins+ patients, ab+/ins− patients had 95% lower GAD titers [2.2 (0.9, 34.0) U/mL vs 38.9 (12.6, 92.4) U/mL, P < 0.05]. ICA titers >20 JDRF units were found in 30 (73%) ab+/ins− and in 41 (100%) ab+/ins+ patients. BMI negatively correlated with GAD titers in ab+/ins− patients (r = −0.47, P < 0.05). Metabolic syndrome components and diabetes-related comorbidities When analyzing further cardiovascular risk factors comprising the so-called metabolic syndrome (25), we observed that there was no difference in waist-to-hip ratio between ab+/ins− patients and patients of the other groups. The lipid profile as presented in Table 1 shows similarities in total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol and triglyceride levels between ab+/ins− and ab−/ins−. Of the ab+/ins− patients, 29 (71%) had fasting triglyceride levels <150 mg/dL (26), and 14 (34%) achieved LDL levels <100 mg/dL as recommended in the European Society of Cardiology guidelines (11). Hypertension was present in 22 (54%) of the patients with ab+/ins−, 14 (34%) of the patients with ab+/ins+, 29 (71%) of the patients with ab−/ins−, and 21 (51%) of the controls. No differences were evident between ab+/ins− patients and patients of the other groups with regard to antihypertensive treatment. Regarding diabetes-related comorbidities, some patients had micro- and macrovascular complications already within the first year after diagnosis: two cases of diabetic retinopathy, one case of diabetic neuropathy, and two cases of myocardial infarction in patients with ab+/ins− (12%); one case of peripheral artery disease and one case of stroke in patients with ab−/ins− (5%); one case of peripheral artery disease in glucose-tolerant controls (2%); and no diagnosed complications in patients with ab+/ins+ (0%). Insulin sensitivity and β-cell function Whole-body insulin sensitivity in ab+/ins− patients was comparable to that of ab+/ins+ patients but 41% higher than in ab−/ins− patients and 16% lower than in controls (Fig. 1A). After further adjustments for fasting blood glucose and HbA1c, only differences between ab+/ins− patients and ab−/ins− patients remained (P < 0.05). Figure 1. View largeDownload slide Metabolic characteristics of patients with newly diagnosed LADA (ab+/ins−), patients with type 1 diabetes (ab+/ins+), patients with type 2 diabetes (ab−/ins−), and controls (con) showing (A) insulin sensitivity (M-value), (B) total C-peptide secretion during IVGTT, and (C) C-peptide and (D) insulin secretion after glucagon stimulation. Box plots show medians and whiskers from minimum to maximum. P values refer to comparison of data adjusted for age, sex, and BMI. Data were ln-transformed where applicable. *P ≤ 0.05, **P ≤ 0.05 after correction for multiple testing. Figure 1. View largeDownload slide Metabolic characteristics of patients with newly diagnosed LADA (ab+/ins−), patients with type 1 diabetes (ab+/ins+), patients with type 2 diabetes (ab−/ins−), and controls (con) showing (A) insulin sensitivity (M-value), (B) total C-peptide secretion during IVGTT, and (C) C-peptide and (D) insulin secretion after glucagon stimulation. Box plots show medians and whiskers from minimum to maximum. P values refer to comparison of data adjusted for age, sex, and BMI. Data were ln-transformed where applicable. *P ≤ 0.05, **P ≤ 0.05 after correction for multiple testing. With regard to β-cell function, total C-peptide secretion during IVGTT (Fig. 1B) was 228% higher in ab+/ins− patients compared with ab+/ins+ patients, 35% lower compared with ab−/ins− patients, and 61% lower compared with controls (all P < 0.05). These differences remained after adjustment for age, sex, and BMI. Similarly, ΔC-peptide levels following glucagon stimulation (Fig. 1C) were 180% higher in ab+/ins− patients compared with ab+/ins+ patients, 31% lower than in ab−/ins− patients, and 53% lower than in controls (all P < 0.05). Furthermore, in patients with ab+/ins−, GAD antibody titers inversely correlated with ΔC-peptide (r = −0.33, P < 0.05) (Fig. 2). Correspondingly, Δinsulin in ab+/ins− patients was 144% higher compared with ab+/ins+ patients, 62% lower than in ab−/ins− patients, and 138% lower than in controls (all P < 0.05) (Fig. 1D). Further analyses with adjustments for fasting glucose confirmed higher insulin secretory response in ab+/ins− compared with ab+/ins+ and controls and similarity between ab+/ins− and ab−/ins−. Figure 2. View largeDownload slide Correlation of GAD antibodies with BMI (A, B), with β-cell function expressed as total C-peptide secretion during the IVGTT (C, D), and with C-peptide secretion upon glucagon stimulation (E, F) in ab+/ins− patients (circles) and ab+/ins+ patients (triangles). (A, E) BMI and glucagon-stimulated C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins− patients. (D) Glucose-stimulated total C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins+ patients. Individual data are presented as scatter plots with linear regression including 95% confidence intervals and with partial Pearson correlations coefficients (r) and corresponding P values. Figure 2. View largeDownload slide Correlation of GAD antibodies with BMI (A, B), with β-cell function expressed as total C-peptide secretion during the IVGTT (C, D), and with C-peptide secretion upon glucagon stimulation (E, F) in ab+/ins− patients (circles) and ab+/ins+ patients (triangles). (A, E) BMI and glucagon-stimulated C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins− patients. (D) Glucose-stimulated total C-peptide secretion inversely correlated with GAD antibody titers in ab+/ins+ patients. Individual data are presented as scatter plots with linear regression including 95% confidence intervals and with partial Pearson correlations coefficients (r) and corresponding P values. Discussion The ab+/ins− patients, reflecting the so-called LADA, as defined by positive diabetes-associated antibodies, age >30 years at diagnosis, and no insulin treatment during the first 6 months upon diabetes diagnosis, had higher insulin sensitivity than matched patients with type 2 diabetes and presented with better β-cell function parameters than patients with type 1 diabetes, independent of BMI. In the ab+/ins− patients, GAD antibody titers were found to inversely correlate with both C-peptide release after glucagon stimulation and BMI. Of note, the high prevalence of diabetes-related complications is noteworthy, despite the lower prevalence of components of the metabolic syndrome in these newly diagnosed ab+/ins− patients (27). Although ab+/ins− patients have a lower body weight and younger age at onset of diabetes than patients with type 2 diabetes (28), previous studies have attributed differences in metabolic parameters to BMI (14). Consequently, we adjusted our analyses to account for this confounding factor. Also, similar to the study by Hawa et al. (28), we found an inverse association between BMI and the GAD autoantibody titer, indicating that ab+/ins− patients with lower β-cell–directed immunoreactivity are closer to the typical phenotype of type 2 diabetes. Previous studies revealed contradictory data on the relationship between BMI and GAD autoantibodies, either in favor (29) or against (30) a role of obesity as an accelerator of insulin resistance, thereby driving the immune response and promoting β-cell apoptosis. Although the cross-sectional design does not allow us to establish causality, the current study detected an interaction between BMI, GAD autoantibody titers, and β-cell function. Adjusting for ΔC-peptide abolished the correlation between BMI and GAD autoantibodies, suggesting that this correlation is mediated by impaired β-cell function. In line, a direct relationship between BMI and ΔC-peptide has been reported (31). Because of its prospective design (18), the source study of this analysis, the GDS, should be able to address at least some aspects of the role of obesity for diabetes-related autoimmunity and β-cell function in the future. Previous studies implied that the onset of disease in patients with adult-onset autoimmune diabetes can be insidious, similar to that observed in patients with type 2 diabetes, which promotes a postponed medical attendance and possibly a delayed initiation of adequate treatment (5). Nevertheless, we showed that latency of diagnosis following the first appearance of diabetes-related symptoms was not different between ab+/ins− and ab−/ins− patients, and neither were family history of diabetes nor HbA1c levels. Therefore, the clinical appearance does not show clear criteria to distinguish latent autoimmune diabetes from type 2 diabetes. The methods of achieving glycemic control have been viewed with controversy in ab+/ins− patients because there is no consensus on therapeutic strategies (32). Previous studies have reported insufficient glycemic control in ab+/ins− patients, endorsing immediate insulin treatment (9). In contrast, in our cohort, HbA1c levels in ab+/ins− patients were comparable to those of ab−/ins− patients and well within the guideline-imposed limits for glycemic control (11). Furthermore, there was no difference in those patients incorrectly attributed to type 2 diabetes compared with those attributed to so-called LADA. Although guidelines (11) advocate for distinguishing patients presenting with diabetes-associated antibodies from type 2 diabetes, in our cohort, most ab+/ins− patients were initially diagnosed as having type 2 diabetes. Even without insulin treatment 6 months from disease onset, 73% of the ab+/ins− patients achieve excellent glycemic control when treated with biguanides, sulphonylureas, and/or dipeptidylpeptidase-4 inhibitor (10, 33). Previous studies on ab+/ins− patients have described pronounced dyslipidemia (34), which is regarded as an important atherogenic risk factor. This, coupled with reduced insulin sensitivity and hypertension, can contribute to an increased cardiovascular risk (35), increasing the hazard for vascular events. Our findings are in line with a Spanish study, which showed only satisfactory lipid control in ab+/ins− patients even after several years of disease duration (36). Similarly, ab+/ins− patients of our study had a heterogeneous lipid profile, with lower LDL levels than ab+/ins+ patients independent of age, BMI, and waist-to-hip ratio, and presumably benefited from the lipid-lowering therapy but at the same time had lower high-density lipoprotein levels than patients with type 2 diabetes. Our results warrant further research into the factors influencing the lipid profile of ab+/ins− patients, as we showed the presence of micro- and macrovascular complications in 12% of these patients already within the first year after diagnosis. However, this study was not powered to compare the prevalence of diabetes-related complications between the groups. Up to now, ab+/ins− patients have been scarcely investigated with regard to insulin sensitivity. There is compelling evidence that insulin resistance can be present in both type 2 diabetes and type 1 diabetes (37), although to a lesser degree in the latter. Our results suggest that a higher BMI is not the main contender in determining insulin resistance in adult-onset autoimmune diabetes. Even though ab+/ins− patients had higher whole-body insulin sensitivity than their type 2 diabetes counterparts of similar age, they also had a lower insulin sensitivity than age- and BMI-matched controls. The effect of elevated fasting glucose and glycemic control on the group comparison analyses indicates that hyperglycemia may at least contribute to the reduced insulin sensitivity in ab+ patients. Given the short known disease duration of these patients, these findings suggest an important role of glucose toxicity even in the early course of disease. There are contradicting data on describing LADA as a distinct disease entity with a unique metabolism, as it encompasses features that are present in both type 1 and type 2 diabetes. Interestingly, our ab+/ins− patients showed both better insulin sensitivity and preserved β-cell function, distinct from patients with type 2 diabetes, independent of age, sex, or BMI. The preserved residual capacity of C-peptide stimulation in ab+/ins− patients reflects a decelerated loss of β-cell functionality compared with type 1 diabetes. Nonetheless, patients with autoimmune diabetes who have a reduced C-peptide secretion will be prone to a shorter interval of insulin-free therapy than patients with type 2 diabetes (38). Despite the presence of β-cell-directed autoimmunity, confirmed by the presence of diabetes-associated autoantibodies, there seems to be only a mild autoimmune reactivity. The differences between ab+/ins− patients and controls were preserved after adjustments for fasting blood glucose with correction for multiple analysis, thereby ruling out a relevant role of the fasting blood glucose level as a confounding factor for β-cell function. The strength of our study design relies on the well-characterized metabolism of ab+/ins− patients in comparison with matched patients with type 1 and type 2 diabetes and healthy controls. Patients included in the study had similar disease duration and had undergone gold-standard methods following standard operating procedures to evaluate β-cell function and insulin sensitivity. The specific metabolic features of ab+/ins− patients should raise clinical awareness. These patients will not benefit from insulin substitution based on established dosing algorithms for type 1 diabetes but will require more individualized treatment, taking into account their lower insulin sensitivity. Furthermore, in the presence of diabetes-related autoimmunity, patients may also need intensive lifestyle modification and monitoring of both physical fitness and body fat mass to improve their insulin resistance. Although the 8.3% prevalence of ab+/ins− in patients with type 2 diabetes of the GDC cohort lies in the range of previously described studies, the relatively small number of subjects is a limitation of the study. In conclusion, adult patients with recently diagnosed autoimmune diabetes have higher insulin sensitivity than patients with type 2 diabetes, but specifically, patients with autoimmune diabetes without initial insulin treatment (previously termed LADA) have a partly preserved β-cell function at the onset of diabetes. Compared with healthy humans, these ab+/ins− patients show impaired whole-body insulin sensitivity possibly due to chronic hyperglycemia. Abbreviations: ab−/ins− antibody negative/insulin negative ab+/ins− antibody positive/insulin negative ab+/ins+ antibody positive/insulin positive BMI body mass index GAD glutamic acid decarboxylase GDS German Diabetes Study HbA1c hemoglobin A1c hsCRP high-sensitivity C-reactive protein ICA islet-cell antigen IVGTT intravenous glucose tolerance test JDRF Juvenile Diabetes Research Foundation LADA latent autoimmune diabetes of the adult LDL low-density lipoprotein. Acknowledgments Financial Support: The GDS was initiated and financed by the DDZ–German Diabetes Center, which is funded by the German Federal Ministry of Health (Berlin, Germany) and the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany) and from the German Federal Ministry of Education and Research (BMBF) grant to the German Center for Diabetes Research (DZD e.V.) and the Schmutzler Stiftung, Germany. Clinical Trial Information: ClinicalTrials.gov no. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Feb 1, 2018

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