Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes

Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ–positive, multiautoantibody-positive) and partially regulated (interleukin-10–positive, pauci-autoantibody–positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed “hyper-immune CD20Hi” and “pauci-immune CD20Lo.” Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.     

Global Biochemical Profiling Identifies β-Hydroxypyruvate as a Potential Mediator of Type 2 Diabetes in Mice and Humans

Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the “incretin response.” To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin–expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. β-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting β-hydroxypyruvate production from d-serine. In vitro, β-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. β-Hydroxypyruvate–to–d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to β-hydroxypyruvate–to–d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and β-cells by regulating β-hydroxypyruvate levels.     

Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel

A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving form of autoimmune diabetes, described as latent autoimmune diabetes of adults (LADA), accounts for 2–12% of all patients with adult-onset diabetes, though they show considerable variability according to their demographics and mode of ascertainment. While therapeutic strategies aim for metabolic control and preservation of residual insulin secretory capacity, endotype heterogeneity within LADA implies a personalized approach to treatment. Faced with a paucity of large-scale clinical trials in LADA, an expert panel reviewed data and delineated one therapeutic approach. Building on the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus for T2D and heterogeneity within autoimmune diabetes, we propose “deviations” for LADA from those guidelines. Within LADA, C-peptide values, proxy for β-cell function, drive therapeutic decisions. Three broad categories of random C-peptide levels were introduced by the panel: 1) C-peptide levels <0.3 nmol/L: a multiple-insulin regimen recommended as for T1D; 2) C-peptide values ≥0.3 and ≤0.7 nmol/L: defined by the panel as a “gray area” in which a modified ADA/EASD algorithm for T2D is recommended; consider insulin in combination with other therapies to modulate β-cell failure and limit diabetic complications; 3) C-peptide values >0.7 nmol/L: suggests a modified ADA/EASD algorithm as for T2D but allowing for the potentially progressive nature of LADA by monitoring C-peptide to adjust treatment. The panel concluded by advising general screening for LADA in newly diagnosed non–insulin-requiring diabetes and, importantly, that large randomized clinical trials are warranted.     

A Genome-Wide Association Study in American Indians Implicates DNER as a Susceptibility Locus for Type 2 Diabetes

Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls, and a family-based association test was conducted. Tag SNPs (n = 311) were selected for 499 SNPs associated with diabetes (P < 0.0005 in case-control analyses or P < 0.0003 in family-based analyses), and these SNPs were genotyped in up to 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10⁻⁸, which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.     

Can Roux-en-Y gastric bypass provide a lifelong solution for diabetes mellitus?

Background

The surgical treatment of diabetes had witnessed progressive development and success since the first case of pancreatic transplantation. Although this was a great step, wide clinical application was limited by several factors. Bariatric surgery such as gastric bypass is emerging as a promising option in obese patients with type 2 diabetes. The aim of this article is to explore the current application of gastric bypass in patients with type 2 diabetes and the theoretical bases of gastric bypass as a treatment option for type 1 diabetes.

Methods

We performed a MEDLINE search for articles published from August 1955 to December 2008 using the words “surgical treatment of diabetes,” “etiology of diabetes” and “gastric bypass.”

Results

We identified 3215 studies and selected 72 relevant papers for review. Surgical treatment of diabetes is evolving from complex pancreatic and islets transplantation surgery for type 1 diabetes with critical postoperative outcome and follow-up to a metabolic surgery, including gastric bypass. Gastric bypass (no immune suppression or graft rejection) has proven to be highly effective treatment for obese patients and nonobese animals with type 2 diabetes. There are certain shared criteria between types 1 and 2 diabetes, making a selected spectrum of the disease a potential target for metabolic surgery to improve or cure diabetes.

Conclusion

Roux-en-Y gastric bypass is a promising option for lifelong treatment of type 2 diabetes. It has the potential to improve or cure a selected spectrum of type 1 diabetes when performed early in the disease. Further animal model studies or randomized controlled trials are needed to support our conclusion.     

Diabetes mellitus in Nigeria: The past,present and future

Diabetes mellitus (DM) is a diverse group of metabolic disorders that is often associated with a high disease burden in developing countries such as Nigeria. In the early nineties, not much was known about DM in Nigeria and traditionally, people related DM to “curses” or “hexes” and diagnosis was made based on blood or urinary tests for glucose. Currently, oral hypoglycaemic agents but not insulin are readily accessible and acceptable to persons with DM. The cost of diabetes care is borne in most instances by individuals and often payment is “out of pocket”-this being a sequel of a poorly functional national health insurance scheme. An insulin requiring individual on a minimum wage would spend 29% of his monthly income on insulin. Complementary and alternative medicines are widely used by persons with DM and form an integral component of DM care. Towards reducing the burden of DM in Nigeria, we suggest that there be concerted efforts by healthcare professionals and stakeholders in the health industry to put in place preventative measures, a better functioning health insurance scheme and a structured DM program.     

Epithelial Dysplasia in Actinic Cheilitis: Microscopic Study of 70 Cases from Brazil

To compare two grading systems of epithelial dysplasia—World Health Organization (WHO) and binary system (BS) –in actinic cheilitis (AC). Seventy cases diagnosed as AC in an Oral Pathology Laboratory from Brazil in the last 12 years were retrospectively retrieved, including the demographic data of each patient. All conventionally stained slides were reviewed, and epithelial dysplasia was evaluated by two independent observers using both WHO and BS grading systems. Data correlation was performed using kappa and chi-square tests (p < 0.05). Most patients were white men with a mean age of 57 years old and history of chronic exposure to sunlight. Most of the lesions were clinically described as whitish plaques with irregular surface located in the lower lip semi-mucosa. Most cases were microscopically graded as severe epithelial dysplasia and low-risk by both observers. The interobserver and intraobserver agreement between systems was slight. All reddish lesions were graded as severe epithelial dysplasia, showing an equal distribution between low and high-risk grading. Most ulcerated lesions showed severe epithelial dysplasia but was graded as low-risk of malignant transformation. Statistical significance was observed among the presence of “irregular stratification”, severe epithelial dysplasia and high-risk lesions (p < 0.05) likewise among the presence of “loss of polarity of basal cells” and “drop-shaped ridges” (p < 0.05) with high-risk lesions. The absence of “increased mitotic figures”, “dyskeratosis” and “keratin pearls” (p < 0.05) were strongly correlated to low-risk lesions. The presence of “hyperchromasia” was statistically significant with severe epithelial dysplasia (p < 0.05) as well the absence of “atypical mitotic figures” with low-risk lesions (p < 0.05). Although there was slight agreement between microscopic grading systems, microscopic analysis indicated that architectural epithelial changes individually may be the more reliable criteria to indicate the risk of malignant transformation in AC in both grading systems.Electronic supplementary materialThe online version of this article (10.1007/s12105-020-01250-z) contains supplementary material, which is available to authorized users.     

Spinal cord involvement in Lewy body-related α-synucleinopathies

Context: Lewy body (LB)-related α-synucleinopathy (LBAS) is the neuropathological hallmark of several neurodegenerative diseases such as Parkinson disease (PD), but it is also found in neurologically asymptomatic subjects. An abnormal accumulation of α-synuclein has been reported also in the spinal cord, but extent and significance of the spinal cord involvement are still poorly defined.Objective: We aimed to review the studies addressing the spinal cord involvement of LBAS in healthy subjects and in patients with PD or other neurodegenerative diseases.Methods: A MEDLINE search was performed using following terms: “spinal cord”, “ α-synucleinopathy”, “α-synuclein”, “Lewy body”, “Parkinson’s disease”, “multiple system atrophy”, “neurodegenerative disorder”.Results: LBAS in the spinal cord is associated with that of the medullary reticular formation and locus ceruleus in the brainstem but not with that in the olfactory bulb and amygdala. The intermediolateral columns of the thoracic and sacral cord are the most frequently and severely affected region of the spinal cord. LBAS occurs in centrally projecting spinal cord neurons integrating pain, in particular from lower body periphery. It also involves the sacral parasympathetic nucleus innervating the smooth muscles of the bladder and distal colon and the Onuf’s nucleus innervating the striated sphincters. The spinal cord lesions may thus play a crucial role in the genesis of frequent non-motor symptoms such as pain, urinary symptoms, bowel dysfunction, autonomic failure including orthostatic hypotension and sexual disturbances. Moreover, these may also contribute to the motor symptoms, since α-synuclein inclusions have been observed in the pyramidal tracts of patients with PD and multiple system atrophy.Conclusion: Recognition of this peculiar spinal cord pathology may help in the management of the related symptoms in subjects affected by α-synucleinopathies.     

Neutrophil Priming by Cytokines in Patients With Obstructive Jaundice

Patients with obstructive jaundice frequently suffer postoperative complications. We have investigated the relationship of obstructive jaundice to the neutrophil oxidase response and the “priming” of the response by the cytokines TNFα, interleukin-1 (IL-1), IL-6, and IL-8. On stimulation with f-met-leuphe (fmlp), the respiratory burst in neutrophils from jaundiced patients was greatly increased compared with controls (p < 0.01), jaundiced patients having the highest respiratory burst levels were those with the poorest prognosis. Neutrophils from controls were primed by all the cytokines tested, whereas “jaundiced” cells were primed only by IL-1, and not by TNFα, IL-6, or IL-8, which in fact produced slight inhibition. We conclude that neutrophils from obstructive jaundiced patients have raised oxidative responses which may be due to “pre-priming” in vivo by cytokines, such as IL-6, IL-8, or TNFα. This exaggeration of the oxidative response in circulating neutrophils may contribute to the peri-operate complications of patients with obstructive jaundice.     

Response to comment on: Statin use and risk of diabetes mellitus

In letter to the editor “Comment on: Statin use and risk of diabetes mellitus” authors found the statement “pravastatin 40 mg/d reduced the risk of diabetes by 30% in West of Scotland Coronary Prevention study” erroneous. As per our opinion the statement is right but had been referenced incorrectly.     

Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes

Diabetic foot ulcerations have been extensively reported as vascular complications of diabetes mellitus associated with a high degree of morbidity and mortality. Diabetic foot syndrome (DFS), as defined by the World Health Organization, is an “ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischemia and infection”. Pathogenic events able to cause diabetic foot ulcers are multifactorial. Among the commonest causes of this pathogenic pathway it’s possible to consider peripheral neuropathy, foot deformity, abnormal foot pressures, abnormal joint mobility, trauma, peripheral artery disease. Several studies reported how diabetic patients show a higher mortality rate compared to patients without diabetes and in particular these studies under filled how cardiovascular mortality and morbidity is 2-4 times higher among patients affected by type 2 diabetes mellitus. This higher degree of cardiovascular morbidity has been explained as due to the observed higher prevalence of major cardiovascular risk factor, of asymptomatic findings of cardiovascular diseases, and of prevalence and incidence of cardiovascular and cerebrovascular events in diabetic patients with foot complications. In diabetes a fundamental pathogenic pathway of most of vascular complications has been reported as linked to a complex interplay of inflammatory, metabolic and procoagulant variables. These pathogenetic aspects have a direct interplay with an insulin resistance, subsequent obesity, diabetes, hypertension, prothrombotic state and blood lipid disorder. Involvement of inflammatory markers such as IL-6 plasma levels and resistin in diabetic subjects as reported by Tuttolomondo et al confirmed the pathogenetic issue of the a “adipo-vascular” axis that may contribute to cardiovascular risk in patients with type 2 diabetes. This “adipo-vascular axis” in patients with type 2 diabetes has been reported as characterized by lower plasma levels of adiponectin and higher plasma levels of interleukin-6 thus linking foot ulcers pathogenesis to microvascular and inflammatory events. The purpose of this review is to highlight the immune inflammatory features of DFS and its possible role as a marker of cardiovascular risk in diabetes patients and to focus the management of major complications related to diabetes such as infections and peripheral arteriopathy.     

Risk of Adverse Pregnancy Outcomes in Women with CKD

CKD is increasingly prevalent in pregnancy. In the Torino-Cagliari Observational Study (TOCOS), we assessed whether the risk for adverse pregnancy outcomes is associated with CKD by comparing pregnancy outcomes of 504 pregnancies in women with CKD to outcomes of 836 low-risk pregnancies in women without CKD. The presence of hypertension, proteinuria (>1 g/d), systemic disease, and CKD stage (at referral) were assessed at baseline. The following outcomes were studied: cesarean section, preterm delivery, and early preterm delivery; small for gestational age (SGA); need for neonatal intensive care unit (NICU); new onset of hypertension; new onset/doubling of proteinuria; CKD stage shift; “general” combined outcome (preterm delivery, NICU, SGA); and “severe” combined outcome (early preterm delivery, NICU, SGA). The risk for adverse outcomes increased across stages (for stage 1 versus stages 4–5: “general” combined outcome, 34.1% versus 90.0%; “severe” combined outcome, 21.4% versus 80.0%; P<0.001). In women with stage 1 CKD, preterm delivery was associated with baseline hypertension (odds ratio [OR], 3.42; 95% confidence interval [95% CI], 1.87 to 6.21), systemic disease (OR, 3.13; 95% CI, 1.51 to 6.50), and proteinuria (OR, 3.69; 95% CI, 1.63 to 8.36). However, stage 1 CKD remained associated with adverse pregnancy outcomes (general combined outcome) in women without baseline hypertension, proteinuria, or systemic disease (OR, 1.88; 95% CI, 1.27 to 2.79). The risk of intrauterine death did not differ between patients and controls. Findings from this prospective study suggest a “baseline risk” for adverse pregnancy-related outcomes linked to CKD.     

Changes in Health-Related Quality of Life (HRQOL) of a Specific Group of Adolescent Idiopathic Scoliosis (AIS) Patients Who Came Across Both Bracing and Surgery

Background/Purpose of the StudyChanges in health-related quality of life (HRQOL) of AIS patients coming across both bracing and surgery have not yet reported. These patients received two major clinical interventions and their HRQOL might be different from previous articles. The aim of this study is to evaluate the changes of HRQOL of a specific group of AIS patients who experienced both bracing and surgery.MethodsOne hundred and twenty-eight patients requiring surgery with prior bracing treatment were identified from the electronic record. SRS-22 questionnaire was completed at 7 time points crossing both interventions (namely “Before”, “Bracing ≤ 1 year”, “Bracing > 1 year”, “Pre-op”, “Post-op”, “Post-op ≤ 1 year, and “Post-op 1-2 years”).ResultsSRS-22 “Function”, “Pain” and “Self-image” scores were decreased from “Before” to “Bracing ≤ 1 year” when started bracing and raised at “Bracing > 1 year”. The 3 scores were dropped from “Bracing > 1 year” to “Pre-op”, particularly on “Self-image”. “Function” and “Pain” were significantly dropped from “Pre-op” to “Post-op” and kept raising until “Post-op 1–2 years”. “Self-image” was improving after “Pre-op”. “Mental” was relatively stable along the timeline.ConclusionThis study described the changes in HRQOL of a specific group of AIS patients. Scores were dropped after the two major clinical interventions and recovered afterwards. Medical professionals were able to plan and provide appropriate supports on the expected changes in HRQOL, especially on function, pain and mental.     

HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients

AIM: To investigate whether the presence of human leukocyte antigen(HLA) marker could add new information to discriminated atypical diabetic type 2 patients.METHODS: We analyzed 199 patients initially diagnosed as type 2 diabetes who are treated in special care diabetes clinics(3rd level). This population was classified in "atypical"(sample A) and "classic"(sample B) according to HLA typing. We consider "classic patient" when has absence of type 1 diabetes associated HLA alleles and no difficulties in their diagnosis and treatments. By the other hand, we considered "atypical patient" when show type 1 diabetes associated HLA alleles and difficulties in their diagnosis and treatments. The standard protocol Asociacion Latinoamericana de Diabetes 2006 was used for patients follow up. To analyze differences between both populations in paraclinical parameters we used unpaired t tests and contingence tables. Bivariate and multivariate analyses were carried out using the SPSS software program. In all studies we assume differences statistically significant, with a P-value 0.05 corrected and 95%CI.RESULTS: The typing HLA in the "atypical" populations show that 92.47% patients presented at list one type 1 diabetes associated HLA alleles(DQB1*0201-0302 and DR 3-4) and 7.53% had two of its. The results showed for categorical variables(family history, presence or absence of hypertension and/or dyslipidemia, reason for initial consultation) the only difference found was at dyslipidemia(OR = 0.45, 0.243 OD 0.822(P 0.001). In relation to continuous variables we found significant differences between atypical vs classic only in cholesterol(5.07 ± 1.1 vs 5.56 ± 1.5, P 0.05), high density lipoproteins(1.23 ± 0.3 vs 1.33 ± 0.3, P 0.05) and low density lipoproteins(2.86 ± 0.9 vs 3.38 ± 1.7, P 0.01). None of the variables had discriminating power when logistic regression was done.CONCLUSION: We propose an algorithm including HLA genotyping as a tool to discriminate atypical patients, complementing international treatment guidelines for complex patients.     

Association of 1,5-Anhydroglucitol With Cardiovascular Disease and Mortality

In diabetes, low concentrations of the biomarker 1,5-anhydroglucitol (1,5-AG) reflect hyperglycemic excursions over the prior 1–2 weeks. To the extent that hyperglycemic excursions are important in atherogenesis, 1,5-AG may provide independent information regarding cardiovascular risk. Nonetheless, few studies have evaluated associations of 1,5-AG with long-term cardiovascular outcomes in a population-based setting. We measured 1,5-AG in 11,106 participants in the Atherosclerosis Risk in Communities (ARIC) study without cardiovascular disease at baseline (1990–1992) and examined prospective associations with coronary heart disease (n = 1,159 events), ischemic stroke (n = 637), heart failure (n = 1,553), and death (n = 3,120) over 20 years of follow-up. Cox proportional hazards models were adjusted for demographic and cardiovascular risk factors. Compared with persons with 1,5-AG ≥6 μg/mL and no history of diabetes, persons with diabetes and 1,5-AG <6.0 μg/mL had an increased risk of coronary heart disease (HR 3.85, 95% CI 3.11–4.78), stroke (HR 3.48, 95% CI 2.66–4.55), heart failure (HR 3.50, 95% CI 2.93–4.17), and death (HR 2.44, 95% CI 2.11–2.83). There was a threshold effect, with little evidence for associations at “nondiabetic” concentrations of 1,5-AG (e.g., >10 μg/mL). Associations remained but were attenuated with additional adjustment for fasting glucose or HbA_1c. These data add to the growing evidence for the prognostic value of 1,5-AG for long-term complications in the setting of diabetes.     

The Streetlight Effect in Type 1 Diabetes

In the nearly 100 years since the discovery of therapeutic insulin, significant research efforts have been directed at finding the underlying cause of type 1 diabetes (T1D) and developing a “cure” for the disease. While progress has clearly been made toward each of these goals, neither vision has been fulfilled. With increasing pressure from both public and private funders of diabetes research, growing impatience of those with T1D at the lack of practical discoveries, increased competition for research funds, uncertainties on the reproducibility of published scientific data, and questions regarding the value of animal models, the current research environment has become extraordinarily difficult to traverse from the perspective of investigators. As a result, there is an increasing pressure toward performance of what might be considered “safe” research, where the aim is to affirm existing dogmas rather than to pioneer efforts involving unconventional thought. Psychologists refer to this practice as “observational bias” while cartoonists label the process the “streetlight effect.” In this Perspective, we consider notions in T1D research that should be subject to bold question and provide additional concepts, many somewhat orphan to research efforts, whose investigation could lead to a means for truly identifying the cause of and a cure for T1D.     

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA_1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m²) and 10-year historical uACR, HbA_1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E^−/− mice. Kidney biopsies were used to examine infiltration of KIM-1–expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACR_AUC0–10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m² higher estimated glomerular filtration rates (modified Schwartz equation; P_adj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8⁺ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1⁺ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium–glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8⁺ T-cell production of KIM-1.     

HLA Class II Genotyping of African American Type 1 Diabetic Patients Reveals Associations Unique to African Haplotypes

HLA genotyping was performed in African American type 1 diabetic patients (n = 772) and controls (n = 1,641) in the largest study of African Americans and type 1 diabetes reported to date. Cases were from Children’s Hospital and Research Center Oakland and from existing collections (Type 1 Diabetes Genetics Consortium [T1DGC], Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications [DCCT/EDIC], and Genetics of Kidneys in Diabetes [GoKinD]). Controls were from the T1DGC and from newborn bloodspot cards. The diversity of HLA DRB1-DQA1-DQB1 haplotypes and genotypes is far greater than that found in Europeans and European Americans. Association analyses replicated many type 1 diabetes risk effects of European-derived haplotypes but also revealed novel effects for African-derived haplotypes. Notably, the African-specific “DR3” haplotype DRB1*03:02-DQA1*04:01-DQB1*04:02 is protective for type 1 diabetes, in contrast to the common and highly-susceptible DR3 DRB1*03:01-DQA1*05:01-DQB1*02:01. Both DRB1*07:01 and DRB1*13:03 haplotypes are predisposing when they include DQA1*03:01-DQB1*02:01g but are protective with DQA1*02:01-DQB1*02:01g. The heterozygous DR4/DR9 genotype, containing the African-derived “DR9” haplotype DRB1*09:01-DQA1*03:01-DQB1*02:01g, exhibits extremely high risk (odds ratio = 30.88), approaching that for DR3/DR4 in European populations. Disease risk assessment for African Americans differs greatly from risk assessment in European populations. This has profound implications on risk screening programs and underscores the need for high-resolution genotyping of multiple populations for the rational design of screening programs with tests that will fairly represent the population being screened.Type 1 diabetes is an autoimmune disease characterized by destruction of insulin-producing β-cells. The incidence and prevalence of type 1 diabetes are much higher for populations of European descent than for other ethnic groups (1). In the United States, diabetes mellitus is more common among nonwhite populations, including African Americans, than among non-Hispanic white (European ancestry) populations (2). Because type 2 diabetes is far more prevalent than type 1 diabetes in African American adults, and because the incidence of type 2 diabetes is increasing in African American youth because of the obesity epidemic, the burden of type 1 diabetes in African American youth has been less emphasized in the literature than that of type 2 diabetes (3). However, type 1 diabetes presents a serious burden among African American youth younger than 10 years of age, and African American adolescents are impacted substantially by both type 1 and type 2 diabetes (3). In fact, although type 2 diabetes incidence is increasing, type 1 diabetes is still approximately three-fold more common than type 2 diabetes in the African American pediatric population at Children’s Hospital and Research Center Oakland. Moreover, early disease onset lengthens disease duration and likely leads to complications at relatively young ages. African American individuals with diabetes are at higher risk for the chronic complications of diabetes than are non-Hispanic white (European) Americans, particularly for diabetic nephropathy (4).The incidence of type 1 diabetes varies widely around the world, partly because of ethnic differences in HLA allele and haplotype frequencies across populations. Susceptibility to type 1 diabetes is strongly associated with alleles at the DRB1 locus and at the DQA1 and DQB1 loci, which encode the α-chain and β-chain of the DQ heterodimer. In general, heterodimers that are DQα Arg52–positive and DQβ Asp57–negative represent high genetic risk for type 1 diabetes (5). Because the heterodimeric DQ molecule is encoded by two polymorphic genes, DQA1 and DQB1, individuals heterozygous for DQA1-DQB1 haplotypes have the potential to express up to four different DQ molecules on the cell surface. Heterodimers encoded in trans are postulated to help explain the extremely high risk of the heterozygous “DR3/DR4” genotype, which confers the highest genetic risk known for type 1 diabetes. Data from many reports show that specific combinations of alleles in DRB1-DQA1-DQB1 haplotypes are associated with type 1 diabetes risk.To date, few studies have been reported on HLA association with type 1 diabetes in African Americans, and some early reports may be confounded by the inclusion of type 2 diabetes patients. This study is the largest of its kind reported to date (772 cases, 1,641 controls) and was made possible by combining data from newly collected samples with data from existing collections.