Search

The evidence-based National Diabetes Prevention Program (NDPP) can reduce type 2 diabetes risks, although strategies to improve outcomes are needed. Attendance and weight loss are suboptimal, especially among racial/ethnic minorities, and men are underrepresented (1). Promoting participation with household members may be important given risk concordance (2,3) and benefits of partner/family support in diabetes management interventions (2). Less is known about the role of close others in diabetes prevention. Here, we examined whether engaging in the NDPP with a household member improves outcomes. The NDPP was implemented in a safety net health care system following standard guidelines (4). During 2013–2017, 2,946 adults with diabetes risks (e.g., overweight/obesity, prediabetes) enrolled in classes, available in person at no cost, following outreach from NDPP coaches. Eligible patients were identified from medical records and provider and self-referrals. Individuals in the same class with a shared address were considered dyads. NDPP delivery was otherwise identical whether participants enrolled alone or with a household member. Outcomes included attending ≥1 session, percentage of sessions attended, duration, program completion (≥3 sessions attended in months 1–6 and duration ≥9 months), percent weight loss, and achieving ≥5% weight loss. t tests and χ2 analyses determined demographic differences …

Diabetes accounts for almost 50% of cases of end-stage renal disease (ESRD) in high-income countries (1). Although the impact of intensive glycemic control on macrovascular complications is relatively modest, evidence suggests that tight glucose control may reduce kidney disease progression. The role of glucose control in preventing chronic kidney disease and ESRD continues to be of significant interest. The Veterans Affairs Diabetes Trial (VADT) was a randomized, prospective, multicenter study in 1,791 veterans with poorly controlled type 2 diabetes, primarily to determine the impact of 5.6 years of tight versus standard glycemic control on cardiovascular events; secondary outcomes included microvascular disease. After the 5.6-year interventional period, the cohort was observationally followed for an additional 10 years (median follow-up was 15 years, ending in 2017) and provided a unique view of the impact of glycemic control on important clinical outcomes. As previously reported, baseline demographics, clinical characteristics, statin and blood pressure medicine use, and mean HbA1c (9.4 ± 2% [79.2 mmol/mol]) were balanced between the two groups (2). Participants received either intensive (INT) or standard (STD) glucose control for a median of 5.6 years. The median HbA1c achieved was 1.5% lower in INT versus STD during the intervention phase (6.9% vs. 8.4% [52 vs. 68 mmol/mol]). Subsequent diabetes care was provided by their primary health care team, and participants were followed using the Department of Veterans …

Studies of differences in glycosylated hemoglobin (HbA1c) have defined race/ethnicity as a social construct (1,2), not using objective biological parameters, and thus comparisons may have been confounded (3). Among blacks without diabetes, we investigated whether the proportion of European genetic ancestry (PEA) mediates the sickle cell trait (SCT) and HbA1c relation and whether PEA tracks HbA1c levels over time accounting for SCT. We used data from three Jackson Heart Study (JHS) visits (2000–2004, 2005–2008, and 2009–2013), occurring at 4-year intervals. We excluded participants with diabetes (use of glucose-lowering medication or fasting blood glucose [FBG] ≥126 mg/dL) or prediabetes (FBG ≥100 mg/dL) at visit 1. We estimated PEA using 1,444 ancestry-informative markers. The rs334 variant defined SCT, and rs1050828 indicated glucose-6-phosphate dehydrogenase (G6PD) deficiency. HbA1c was assessed by high-performance liquid chromatography (Tosoh analyzer; assays coefficient of variation 1.4–1.9%). Using visit 1 data, we estimated three relations (Fig. 1 A ) corresponding to regressions of 1 ) SCT on HbA1c ( c ), 2 ) SCT on PEA ( a ), and 3 ) both SCT and PEA on HbA1c levels ( c′ ). The indirect effect of PEA on HbA1c was estimated using the difference between c and c′. Complete mediation is observed when c′ = 0 and partial mediation when c − c′ ≠ 0 (Fig. 1 A ). Figure 1 A : Schematic conceptual framework …

Lower-extremity amputation (LEA) is a devastating complication of peripheral artery disease (PAD). Early identification of PAD patients at high risk of LEA is important to enable targeted monitoring and treatment strategies. Although chronic kidney disease is recognized as a high-risk condition for foot complications in diabetes, most previous studies focused on estimated glomerular filtration rate (eGFR). Proteinuria, a marker of kidney damage, has been less studied than eGFR in this context but is a promising predictor of LEA. A small cross-sectional study in the U.K. suggested that albuminuria was associated with foot ulceration in diabetes (1). A recent meta-analysis showed proteinuria as a strong independent predictor of incident PAD and LEA among those without PAD (2). However, whether proteinuria is associated with LEA among patients with diagnosed PAD is unknown. This is an important clinical question since most PAD patients have diabetes or hypertension, two major clinical conditions that merit proteinuria assessment according to clinical guidelines (3,4), and many of them should have data on proteinuria readily available. Using data from the Geisinger Health System, a fully integrated rural health care system in Pennsylvania (1 March 1997–2 February 2017), we investigated the prospective association between dipstick proteinuria and risk …

Clinicians and global health workers need valid, reliable, readily accessible, and cost-effective indicators to screen for individuals at risk for adverse cardiometabolic events in diverse populations, particularly in resource-poor settings. Waist-to-height ratio (WHtR) has recently emerged as one such promising index in assessing cardiovascular disease (CVD) risk. Meta-analyses of receiver operating characteristic curves showed that WHtR had better power than BMI and waist circumference (WC) in classifying CVD risk factors among adults and children (1,2). However, the role of WHtR in relation to the incidence of CVD has not been examined adequately in well-characterized populations of diverse ethnicities, nor has the strength of association been compared with conventional anthropometric indicators in high-quality prospective cohorts. The national Women’s Health Initiative (WHI) includes 161,808 postmenopausal women across 40 clinical centers in the U.S. who were enrolled at baseline from 1994 to 1998; occurrence of CVD events or death were determined during follow-up (3). Incident CVD events were adjudicated by trained physicians following a standardized protocol. The current study excluded participants with self-reported CVD or cancer at baseline and those who developed CVD or were lost to follow-up within 3 years of enrollment. WHtR, BMI, WC, and waist-to-hip ratio (WHR) were measured at baseline. Changes in body weight were …

Many studies use glucose values from electronic medical record data to identify patients with prediabetes and diabetes (1–3). Since diagnostic criteria are based on fasting glucose (4), investigators often choose to assume that patients were fasting if phlebotomy was performed in the morning. We sought to assess the validity of the assumption that outpatient morning measurements are fasting measures. We surveyed adult patients (age ≥18 years) presenting for phlebotomy at the Johns Hopkins Outpatient Center between 7:00 a.m. and noon over 2 weeks in November 2018. Patients responded to a four-question written survey provided by the registration staff. The survey asked 1 ) about their fasting status, 2 ) whether the ordering provider instructed them to fast, 3 ) whether they were getting a glucose and/or cholesterol test (“If you know which blood test(s) you are getting done, please select ones that are included on the list below,” with answer options of “glucose” and “cholesterol panel”), and 4 ) what …

Several studies in patients with type 1 diabetes have examined the impact of islet transplantation (ITx) on renal function (1–3). Our group and others (1,4) have reported the beneficial effect of ITx. Equally relevant, however, is the assessment of renal function in patients with graft failure (GF) who are exposed to the well-known potential toxicity from immunosuppressive drugs and risk of development or progression of diabetic nephropathy related to unstable glycemic control (5). In this study, we examined the renal function of 12 recipients of allogeneic ITx who developed GF (stimulated C-peptide

Syndromes of severe insulin resistance (IR) include mutations of or autoantibodies to the insulin receptor and lipodystrophy (1). Diabetic ketoacidosis (DKA), although rare, can occur in these patients, even in the context of hyperinsulinemia, due to impaired insulin signaling. DKA can be extremely challenging to treat, and few clinicians are experienced or comfortable in using the high doses of insulin required. We describe aggressive management of DKA in three patients with syndromic severe IR. An 18-year-old man with compound heterozygous mutation of the insulin receptor presented with DKA. He had poorly controlled diabetes (A1C 14% [130 mmol/mol]) treated with U-500 insulin (1,500 units/day), metreleptin (recombinant human methionyl leptin as an experimental drug), and metformin (2 g/day). Two weeks prior, he underwent a root canal for an abscessed tooth but did not take the prescribed antibiotics. Antibiotics were subsequently initiated. One day after discharge, he developed abdominal pain, nausea, vomiting, and worsening jaw pain and swelling. Two days later, he developed fatigue, malaise, and Kussmaul respirations. He presented to an outside hospital with DKA with a pH of 7.08, partial pressure CO2 of 27 mmHg, and bicarbonate of 8 mmol/L. He received fluid resuscitation for an estimated 10% dehydration. In collaboration with National Institutes of Health (NIH) physicians, an insulin drip was started at 100 units/h that was gradually increased to 1,000 units/h on the first day and 2,000 units/h on the second day, without improvement of acidosis (Fig. 1 A ). Because of the lack of improvement despite massive doses of insulin (>50,000 units/day) and intravenous antibiotics, bicarbonate was given and dental extraction performed. He improved thereafter on 2,000 units/h of insulin, which …

Mixed-meal tolerance tests (MMTTs) are used in clinical trials to evaluate β-cell function in patients with new-onset type 1 diabetes (1,2). Some trials use a 4-h MMTT, whereas others use an abbreviated (2-h) protocol to reduce investigator and subject burden. In the T1DAL (Inducing Remission in Type 1 Diabetes With Alefacept) trial of patients with new-onset type 1 diabetes, the primary analysis using the 2-h test failed to reach statistical significance ( P = 0.065), but a 4-h test did ( P = 0.019) (3). We investigated the effect of abbreviating the test using data from 186 patients participating in three clinical trials conducted by the Immune Tolerance Network (3–5). Trials were approved by institutional review boards at the participating institutions. Written informed consent or assent was obtained. Each patient contributed up to three 4-h MMTTs, conducted yearly, for a total of 506 paired 2- and 4-h observations. For this analysis, the 4-h assessment, which captures more of the complete hormonal response, was selected as the reference. The percent of the total 4-h C-peptide area under the curve (AUC) captured in the first 2 h ranged from 28% to 72%. Mean AUCs (mAUCs) were computed as 2- or 4-h AUCs divided by duration, 120 or 240 min, respectively. The correlation between the 2- and 4-h mAUCs was 0.98. Generally, the variability of the 2-h test was greater than that of the 4-h test (Fig. 1 A ). After adjusting for baseline, however, the variability was similar. Figure 1 Analysis of 2- and 4-h C-peptide AUCs during MMTTs. The C-peptide …

Diabetes increases mortality by two- to fourfold from atherosclerosis-related causes, including coronary artery disease, stroke, and peripheral artery disease (1). There is a paucity of population-based data on subclinical atherosclerotic disease in arterial beds other than the coronary arteries in persons with diabetes (2). In the Jackson Heart Study (JHS), we examined the association of diabetes with abdominal aortic calcification (AAC) among African Americans. Among included individuals ( n = 1,664), the mean age was 57 (± 11) years, 69% were female, and 18.3% had diabetes (based on fasting blood glucose [FBG], HbA1c, use of glucose-lowering medications, or physician diagnosis). The median AAC and coronary artery calcification (CAC) scores were 904.15 (interquartile range 0–1093.10) and 0 (0–96.19), respectively. The prevalence of any AAC or CAC was 69% and 49%, respectively. Individuals with diabetes were older, had higher BMI, had higher systolic blood pressure and prevalence of hypertension, had lower …

Older adults with diabetes are at high risk for having multiple chronic conditions and diabetes complications and often take multiple medications concomitantly. Studies have shown that many Americans are using complementary and alternative medicine (CAM) to either improve or manage their health (1,2). Individuals have diverse purposes for using CAM, from treating specific conditions, such as back and neck pain (e.g., acupuncture and chiropractic), to improving general health and wellness (e.g., meditation and tai chi). Since relatively little is known about the prevalence and patterns of CAM use in older adults with diabetes, we investigated this topic to guide integrated, patient-centered health care use for this population. We used data from the 2012 National Health Interview Survey (NHIS), which is an annual cross-sectional in-person interview survey demonstrating health care trends among noninstitutionalized civilians in the U.S. (3). The NHIS collects comprehensive CAM-related information every 5 years. The sample included adults aged 65 or older who reported having …

Historical literature reports risk of fetal demise after diabetic ketoacidosis (DKA) in pregnancy as high as 25–60% (1,2). However, estimates have generally been based on small sample sizes, with limited investigation of other fetal outcomes or risk factors associated with poor fetal outcomes. We aimed to provide an updated assessment of the incidence and risk factors for fetal demise and other adverse outcomes in women with DKA during pregnancy. This retrospective cohort study included pregnancies between 1996 and 2015 with at least one DKA event in women with type 1 diabetes at one of three teaching hospitals in Boston. Data were collected through medical record review. Pregnancies were excluded if information on birth status (live or demise) and gestational age at birth or demise were unknown. Among the 77 DKA events in 64 pregnancies in 62 women included in the study, fetal demise, preterm …

People with severe mental illnesses (SMI) such as schizophrenia and bipolar disorder have an increased risk for diabetes (1), in part due to treatment with both first- and second-generation antipsychotics (2). A large systematic review estimated that 15% of people with SMI have type 2 diabetes, a prevalence double that of age-matched samples from the general population during the same time period (1). Preliminary evidence suggests that racial/ethnic minorities with SMI may be at especially high risk for diabetes compared with whites; unfortunately, similar data regarding prevalence of prediabetes is more limited (2). Understanding of the prevalence of prediabetes and diabetes in a large, racially and ethnically diverse and representative sample is an important first step in reducing diabetes prevalence and related adverse outcomes in this particularly vulnerable population. In this study, we estimate diabetes and prediabetes prevalence among antipsychotic-treated patients within an integrated health care system and determine whether racial/ethnic differences exist. In this retrospective cohort study of adults with SMI in Kaiser Permanente Northern California (KPNC), our primary outcome was evidence of diabetes. The cohort used for this study has been previously described (3). To estimate diabetes prevalence, the primary outcome measure was inclusion in the KPNC diabetes registry at any time before 31 December 2014 (4). To estimate our secondary outcome, prediabetes prevalence, we first excluded people who were in the …

Early markers of diabetic kidney disease (DKD), including hyperfiltration and elevated albumin excretion, are common in youth with type 2 diabetes (T2D) (1). Despite the morbidity associated with the development of future DKD in youth-onset T2D, pharmacotherapeutic options to lower hyperglycemia are limited to metformin and insulin, the only drugs approved for use in pediatric patients. Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce blood pressure, weight, and hyperglycemia in adults with T2D. Furthermore, a 38% reduction in cardiovascular death and a 39% reduction in incident or worsening nephropathy have been demonstrated with the selective SGLT2 inhibitor empagliflozin in patients with established cardiovascular disease (2,3). In young adults with type 1 diabetes, treatment with the SGLT2 inhibitor empagliflozin for 8 weeks was associated with natriuresis, increased renal vascular resistance, and reductions in glomerular filtration rate (GFR) (using inulin clearances) and renal blood flow (assessed by p -aminohippuric acid clearance) in those with baseline hyperfiltration (4). This renal hemodynamic profile suggested that the 20% reduction in hyperfiltration observed in this trial was due to afferent vasoconstriction and a decline in intraglomerular hypertension (4). In adults with T2D, the reduction in intraglomerular hypertension is typically reflected by a mean reduction in estimated GFR (eGFR) of 2–4 mL/min/1.73 m2 after treatment initiation, followed by a stabilization of eGFR decline compared …

Genetics determine only a small proportion of common disease risk, but the potential to motivate health behavior change remains a proposed benefit of genetic susceptibility testing. Evidence supporting this benefit is scant (1), and studies of long-term clinical outcomes are absent. Type 2 diabetes is heritable yet preventable by behavior change. Although genetic scores predict incident diabetes (2), we demonstrated in the Genetic Counseling/Lifestyle Change (GC/LC) Study that learning one’s genetic risk did not impact short-term weight loss or behavior change motivation among participants in a diabetes prevention program (3). Here, we examine 6-year diabetes incidence among participants. The GC/LC Study was a randomized trial of diabetes genetic risk counseling among primary care patients (3). Eligible participants did not have diabetes but were at high phenotypic risk for diabetes in that they were overweight and met at least one other metabolic syndrome criterion. Participants were randomized to undergo genotyping for a diabetes genetic risk score (tested) versus no genotyping (control). Tested participants in …

Over the past two decades, many new treatment options have been introduced for type 2 diabetes. Increasingly, there is debate regarding the effectiveness of insulin as the last-line therapy. While diabetes control has improved over the past two decades (1–3), a substantial portion of patients is still not meeting the clinical targets. To examine national trends in glycemic control by insulin and oral diabetes medication use, we conducted a cross-sectional study of 4,947 adult participants with diagnosed diabetes (all types) in the National Health and Nutrition Examination Survey (NHANES) in the 1988–1994 and 1999–2012 cycles. The NHANES surveys are cross-sectional, complex probability samples of the U.S. civilian noninstitutionalized population. All NHANES protocols were approved by an institutional review board, and informed consent was obtained from participants. Hemoglobin A1c (HbA1c …

Glucagon-like peptide 1 agonists such as exenatide have been reported to improve fasting and postprandial lipid profiles and cardiovascular outcomes in patients with type 2 diabetes but to have minimal effects on fasting profiles in patients with type 1 diabetes based on standard lipid measurements. In this study, we used nuclear magnetic resonance (NMR) to determine the effects of exenatide on lipoprotein particle characteristics, which might be indicative of a change in cardiovascular risk in patients with type 1 diabetes. This is an ancillary study of a previously published clinical trial (ClinicalTrials.gov identifier NCT00064714) (1). Briefly, 14 patients were randomized to receive exenatide (10 µg four times daily) either in the first or the second 6-month study period in addition to insulin (1). The patients were also randomized to treatment with or without the immunomodulatory drug daclizumab for 12 months (1). Patients underwent repeated mixed-meal tests after an overnight fast. Tests were conducted at the beginning and end of each 6-month period. To estimate the mean differences between treatment groups, linear mixed models were used to control for sequence and period effects and to allow for correlation within the same group using Stata's pkcross command for the analysis of crossover experiments. Results are …

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have recently been associated with diabetic ketoacidosis (DKA). Initial case reports were largely among patients using SGLT2i off label in the setting of type 1 diabetes and were unusual because of limited associated hyperglycemia (1). More recently, the problem has been specifically noted in patients with type 2 diabetes (2). Meta-analysis of data from initial randomized controlled trials of SGLT2i suggests little risk of DKA (

Type 1 diabetes (T1D) is associated with a 10-fold increase in cardiovascular disease (CVD) risk, due in part to dyslipidemia. Patients with poorly controlled T1D show an increase in total and LDL cholesterol as well as elevated apolipoprotein B (ApoB) levels. Moreover, even patients with well-controlled T1D can show increased levels of ApoB. Dyslipidemia is particularly important in females with T1D, as the atheroprotective lipoprotein profile and reduced risk of CVD usually observed in females without diabetes are lost in females with diabetes (1,2). Proprotein convertase subtilisin/kexin type 9 (PCSK9) has recently emerged as a novel regulator of plasma cholesterol levels: gain-of-function PCSK9 mutations increase LDL cholesterol and CVD risk, whereas inhibitors of PCSK9 lower LDL cholesterol. Although PCSK9 is increased in individuals with obesity and type 2 diabetes (3,4), it is not known whether PCSK9 levels are also changed in individuals with T1D. Here, we measured PCSK9 levels in a subset of a previously described cohort of T1D and control subjects (5). For the current study, subjects with serum available for PCSK9 measurement were matched for age and sex between each group using the frequency matching method. Subjects who reported taking statin medications at the time of the study were excluded from the analyses ( n = 3, all from T1D …

The Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) studies demonstrated that intensive diabetes management provides for marked reduction in risk for diabetic retinopathy (DR) (1,2). Nevertheless, guidelines for DR screening in the post-DCCT era have remained largely unchanged. Current American Diabetes Association guidelines for youth with type 1 diabetes suggest annual eye exams at the start of puberty or at age ≥10 years, whichever is earlier, once the youth has had diabetes for 3–5 years (3). We sought to examine how often treatable DR was reported among youth enrolled in the TID Exchange Clinic Registry (4). Information about treatment for DR was collected from T1D Exchange Clinic Registry participants via …

Although HbA1c is widely used for diagnosis and management of diabetes in clinical practice and research studies, management of the incidental detection of hemoglobin variants (e.g., hemoglobin S [HbS], HbC) by common HbA1c methods, such as ion exchange high-performance liquid chromatography (HPLC), is not well established. Many clinical laboratories do not report the presence of hemoglobin variants, whereas others report them only if they interfere with HbA1c measurement (1). As routine HbA1c testing may incidentally yield information regarding hemoglobin variants that can affect clinical care, planning for appropriate management is warranted. The Vitamin D and Type 2 Diabetes (D2d) Study is a multicenter, randomized, placebo-controlled trial testing whether vitamin D supplementation reduces diabetes incidence in people at high risk (2). Adults meeting at least two of the three criteria for prediabetes established in 2010 by the American Diabetes Association are eligible for enrollment, and a racially and ethnically diverse study population is sought to ensure generalizability of results. HbA1c testing is performed using an HPLC method (Tosoh G8, Tosoh Bioscience, South San Francisco, CA) at the University of Vermont’s Laboratory for Clinical Biochemistry Research. Review of chromatograms can reveal unexpected peaks reflecting the presence of hemoglobin variants. Although HbS and HbC do not interfere with the assay, the presence of other variants, such as HbE, precludes reporting of HbA1c results. When an abnormal peak is seen, hemoglobin electrophoresis is performed to identify the hemoglobin variant. Because reporting of incidentally detected hemoglobin variants is not standardized, D2d investigators sought consultative opinions from …

Adolescence marks a challenging time in diabetes care (1). Automated insulin delivery has the potential to overcome some of the barriers, such as missed meal boluses and nocturnal hypoglycemia. The University of Virginia Unified Safety System (USS) is one of the most tested control-to-range approaches and operates on an Android-based system that uses a Dexcom G4 PLATINUM Share glucose sensor and Roche Accu-Chek pump (2). The objective of this study was to test the efficacy of USS in day-and-night closed-loop control (CLC) in adolescents with type 1 diabetes at camp, where large meals and physical activity challenge glucose control. In this study, eligible subjects with type 1 diabetes on pump therapy were randomized to either CLC ( n = 17) or sensor-augmented pump (SAP) ( n = 16) for 5 days. There was no A1C restriction. Clinical characteristics of the 33 subjects include mean ± SD (min–max) age of 17.9 ± 5.5 years (10.1–35.0), weight 68 ± 17 kg (37.3–104.3), A1C …

In setting hemoglobin A1c (HbA1c) targets, physicians must consider individualized risks and benefits of tight glycemic control (1,2) by recognizing that the risk-benefit ratio may become unfavorable in certain patients, including the elderly and/or those with multiple comorbidities (3,4). Customization of treatment goals based on patient characteristics is poorly understood, partly due to insufficient data on physicians’ decisions in setting targets. We used the National Health and Nutrition Examination Survey (NHANES) to analyze patient-reported HbA1c targets set by physicians and to test whether targets are correlated with patient characteristics. Data from the NHANES waves 2005–2006, 2007–2008, 2011–2012, and 2013–2014 (the 2009–2010 wave lacked HbA1c data) comprised 2,641 individuals with self-reported diabetes, of which 1,782 responded to the question, “What does [your doctor] say [your] ‘A1C’ level should be?” On the basis of the distribution of responses, we analyzed the following targets

Randomized controlled trials have established the beneficial effect of a healthy diet in the treatment of cardiometabolic disorders. Healthy diet recommendations are based on this evidence (1). However, limited evidence is available on whether individuals with these conditions actually follow such dietary recommendations in an effective way, that is, by making long-term changes in their dietary behavior. In this cohort study of 4,703 participants (mean age 49.5 years, 27.8% women) from the Whitehall II study (www.ucl.ac.uk/whitehallII), we screened participants for type 2 diabetes (T2D), metabolic syndrome (MetS), and obesity and then followed changes in diet with follow-up surveys. Participants were informed that they had diabetes or were obese but were not informed if they had MetS, and no dietary advice was given. Both prevalent (in 1991/1993) and new-onset cases (occurrence between 1991/1993 and 2002/2004) of T2D (according to the World Health Organization criteria [2]), MetS (the National Cholesterol Education Program Adult Treatment Panel III criteria definition), and obesity (BMI ≥30 kg/m2) were considered, as described elsewhere (3). Changes in diet were determined using repeated measures of the Alternative Healthy Eating Index (AHEI) over an 11-year follow-up (from …

Diabetes in childhood has been associated with increased morbidity and mortality, but the risks for diabetes in infancy remain unclear. Cases with onset of hyperglycemia in the first 6 months of life consist predominantly of monogenic diabetes, whereas type 1 autoimmune diabetes accounts for the majority of cases beyond this threshold. Regardless of etiology, diabetes symptoms tend to be difficult to recognize in an infant, putting patients at increased risk for delays in diagnosis, which may lead to higher blood glucose levels and diabetic ketoacidosis (DKA) at presentation. Here, we report a high degree of morbidity among a cohort of subjects with infancy-onset diabetes. We examined diagnosis records from 88 cases with diabetes onset ≤13 months of age collected through the University of Chicago Monogenic Diabetes Registry (1). We assessed laboratory values and sign/symptoms, and if a causal mutation for diabetes was detected, participants were subdivided by similar mutation subtypes. Data were managed using REDCap electronic data capture tools and analyzed using Stata version 14 (StataCorp, 2015). The majority of participants were male ( n = 46, …

Approximately 29 million Americans are diagnosed with diabetes. The increased prevalence of type 2 diabetes (T2D) and required intensity of disease management programs are straining health systems, especially in primary care where physicians often lack adequate time with patients. Mobile technologies (e.g., smartphones, wearable devices) provide highly scalable new approaches to T2D management. Approximately 77% of American adults have access to a smartphone regardless of socioeconomic status or ethnicity (1), and more than 50% of smartphone owners use their mobile devices to obtain health information (2). However, mobile health (mHealth) applications (apps) have been found to lack evidence-based support when functionalities and information provided in apps are compared with clinical guidelines for specific disease management (3). The objective of this study was to assess whether popular apps for diabetes management were of sufficient quality to complement clinical care. We used the Mobile App Rating Scale (MARS) (4), a reliable and validated scoring instrument of mHealth app quality, to assess the quality of the most popular free …

The majority of those with type 1 diabetes (T1D) have suboptimal glycemic control (1–4); therefore, use of adjunctive pharmacotherapy to improve control has been of clinical interest. While noninsulin medications approved for type 2 diabetes have been reported in T1D research and clinical practice (5), little is known about their frequency of use. The T1D Exchange (T1DX) registry in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria are two large consortia of diabetes centers; thus, they provide a rich data set to address this question. For the analysis, 49,996 pediatric and adult patients with diabetes duration ≥1 year and a registry update from 1 April 2015 to 1 July 2016 were included (19,298 individuals from 73 T1DX sites and 30,698 individuals from 354 DPV sites). Adjuvant medication use (metformin, glucagon-like peptide 1 [GLP-1] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT2] inhibitors, and other noninsulin diabetes medications including pramlintide) was extracted from …

The American Diabetes Association’s Standards of Medical Care in Diabetes—2017 states that age should be “taken into consideration” when diagnosing diabetes with HbA1c (1). Nonetheless, it is unclear how this recommendation might be implemented. Population studies demonstrate that HbA1c increases with age, which some experts have suggested may be due to nonglycemic factors like alterations in red cell turnover or hemoglobin glycation (2–4). However, prior studies lack concurrent comparisons across nonhemoglobin-related markers of hyperglycemia. We evaluated increases with age in fructosamine and glycated albumin—hemoglobin-independent measures of hyperglycemia—in comparison with HbA1c and fasting glucose in the community-based Atherosclerosis Risk in Communities (ARIC) study. We conducted serial cross-sectional analyses at visit 2 (1990–1992; n = 11,632) and visit 5 (2011–2013; n = 3,876), excluding individuals with diagnosed diabetes. We performed adjusted linear regression of z scores of each biomarker (standardized to visit 2) on age to allow head-to-head comparisons of the associations. Age was significantly correlated with all biomarkers of hyperglycemia at visit 2 (Fig. 1). In middle …

An improved understanding of which groups are more likely to be unaware of their diabetes may lead to more efficient screening, improved awareness, and overall better treatment for diabetes. Our objective was to investigate factors associated with being unaware of having diabetes among adults with diagnosed and undiagnosed diabetes. The 2011–2014 National Health and Nutrition Examination Survey (NHANES) is a stratified, multistage probability survey representative of the civilian, noninstitutionalized U.S. population (1). Data were collected during an in-home interview and a visit to a mobile examination center. We used data from 1,879 participants with either diagnosed or undiagnosed diabetes (based on a single measurement of A1C, fasting plasma glucose, or 2-h plasma glucose). Using logistic regression, we calculated odds ratios of being unaware of diabetes associated with age, race/ethnicity, sex, gestational diabetes mellitus (GDM), family history of diabetes, education, household income, smoking status, BMI, work-time activity, leisure-time activity, no health insurance, location of routine health …

Intensive glucose control after the onset of type 1 diabetes has been suggested to preserve C-peptide production (1–3). In people with type 1 diabetes, sensor-augmented pump (SAP) use improved glycemic control, particularly when used >6 days/week (4). As previously reported, subjects with type 1 diabetes were randomized to either 3 days of in-hospital hybrid closed-loop therapy followed by SAP therapy or usual care (5). In the primary intent-to-treat analysis, no significant differences existed in HbA1c or C-peptide between the two groups at 1 year. In our post hoc analysis, we hypothesized that more frequent sensor use in the SAP group would be associated with lower HbA1c levels and preservation of C-peptide production at 1 year. Subjects in the SAP group ( n = 46) were stratified by median SAP use of 12.4 h/day. HbA1c and C-peptide levels were compared at baseline and 3, 6, 9, 12, and 24 months. At 12 months of follow-up, the median HbA1c values for those with SAP …

Geographical differences in type 1 diabetes (T1D) prevalence in Europe have been well documented, but little is known about the geographical distribution of autoantibodies specific to GAD65 (GAD65Ab) in the general population without diabetes, which is reported to range between 0.4 and 3%. However, these studies used different methods to define GAD65Ab positivity with cutoff values based on the 97–99th centile or at +3 SD above the mean among healthy individuals without T1D or type 2 diabetes (T2D). In doing so, the prevalence of GAD65Ab among the study cohorts was, by definition, 1–3%. The application of different cutoff levels greatly impairs the direct comparison of prevalence data between studies. Our aims were to 1) explore the prevalence of GAD65Ab positivity using a cutoff defined by specific competition of antibody binding to radiolabeled GAD65 with added autoantigen across eight European countries and 2) compare characteristics of age, sex, and BMI in relation to GAD65Ab positivity. A center-stratified random subcohort of 16,835 (4.9%) individuals was selected from the original European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study (1). After exclusion of individuals with known diabetes, GAD65Ab were analyzed in 15,802 (men/women 5,927/9,875, mean age 52.4 ± 9.2 years) samples. The cutoff for GAD65Ab positivity was determined through a competition assay at ≥65 WHO units/mL, and all samples were analyzed at a single laboratory using a radioligand binding assay (2).In all, 316/15,802 (2.0%) samples were GAD65Ab positive. Sweden, Denmark, U.K., and Spain had the highest and France had the lowest prevalence of GAD65Ab positivity (Table 1); however, these differences were not statistically significant (P = 0.80). We did not detect any association between GAD65Ab positivity and age, sex, or BMI.

In sub-Saharan Africa, projections anticipate a 110% rise in the number of people with diabetes mellitus (DM) from 19.8 million to 41.5 million by 2035 (1). This growth is attributed primarily to the multiple downstream ramifications of urbanization and westernization. Poor access to medications, finances, transportation, and skilled health care providers trained in DM management is a barrier that contributes to poor outcomes for patients with DM (2). As a result, patients are often forced to rely on self-management without guidance from the formal health care sector. To combat this barrier, diabetes self-management support (DSMS) programs sustain psychosocial support and education by incorporating lay DM patients as peer support group leaders at the community level (3,4). Limited data exist for DSMS outcomes in low- and middle-income countries (LMICs). The imminent rise of DM and the logistical challenges of health delivery in …

Chromosome 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI (1). After remitting in infancy, diabetes recurs in most patients later in life. While the best treatment remains unknown, many patients are managed with insulin (1). We sought to characterize β-cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy. Adults with 6q24-TND and recurrence of hyperglycemia requiring insulin therapy later in life were identified through The University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry) and invited to participate in a trial of SU therapy. Four patients with insulin doses of 0.41–0.76 units/kg/day attempted the trial. Three were available for a mixed-meal test (MMT) and arginine stimulation test (AST) on day one and day five of SU treatment. All insulin products were withheld on the morning of day one. Subjects ingested 7 mL/kg (maximal 360 mL) of BOOST High Protein (http://www.boost.com) within 5 …

Glycemic control improves immediately after gastric bypass in patients with type 2 diabetes mellitus (T2DM) (1). The American Diabetes Association defines complete remission of diabetes as a return to normal glucose levels (HbA1c < 6%, fasting glucose

Plantar shear stress has been held accountable as a causative factor in diabetic foot ulcers (DFU) (1,2). Delbridge et al. (2) recognized shear stress as a major causative factor by stating that it is shear rather than vertical load that is responsible for tissue breakdown that occurs deep to the skin. Historically, research in this area has been hampered by an underestimation of the importance of shear stress and the lack of technology to measure it. Emerging evidence within the past decade has demonstrated the clinical significance of shear to foot ulceration (3–5). We previously revealed that individuals with diabetic neuropathy (DN) experience higher plantar shear compared with control subjects (5). However, to our knowledge, no study has compared peak shear in individuals with a history of DFU to those patients with DN but no history of DFU. We quantified peak plantar shear (PS) in 9 subjects with (DFU) and 16 DN subjects without (DN) previous ulcers …

Seasonal variation in glycemic control has been postulated to occur in school-aged children with type 1 diabetes, with higher HbA1c levels during summer months than during the school year because of lack of structure and less stringent adherence to a prescribed medical regimen during summer vacation (1). To address this question, we used data obtained in 1,972 youth with type 1 diabetes enrolled in the T1D Exchange (T1DX) at 56 clinical centers in the U.S. between 2010 and 2012 (2). To be included in these analyses, participants had to be 8 to 3 years to minimize the influence of changes in residual endogenous insulin secretion over time, and have HbA1c measurements in each of three predefined periods: prior to the start of summer (March, April, May), end of summer vacation (August and September), and back in school (November and December). HbA1c values …

Medalists represent a unique group of survivors of over 50 years of type 1 diabetes (T1D) (1,2). A subgroup of Medalists, escapers , remains free of micro- and macrovascular complications. To date, there are no published studies on cardiac structure and function in these subjects. We have undertaken a comprehensive multiparametric cardiac MRI study (3,4) to quantify myocardial structure, function, deformation, perfusion, and fibrosis in a cohort of 13 subjects with extreme-duration T1D and 14 healthy control subjects (Table 1). View this table: Table 1 Clinical characteristics and cardiac MRI data The T1D group had a mean duration of diabetes of 47.4 ± 5.1 years (median 48.0 years). Eight participants had a history of retinopathy and 12 were receiving statin and ACE inhibitor therapy. The mean HbA1c over the previous 16 years was 8.3 ± …

Continuous glucose monitoring (CGM) technology provides real-time glucose data and the ability to achieve improved glycemic control; however, widespread adoption has been limited (1). Among the challenges to CGM uptake are cost and the inconvenience of changing the sensor. In this prospective, multicenter study, the Dexcom G4 PLATINUM system was analyzed over 14 days of continuous sensor wear. Each subject wore two sensors simultaneously. After 7 days, subjects left their original sensors in place and began a second 7-day sensor session. This procedure was then repeated with two new sensors for a second 2-week period. Blood glucose (BG) readings from Bayer CONTOUR NEXT meters served as reference (2), with absolute relative difference (ARD) defined as the percent error between sensor and matched BG values. The Mann-Whitney rank sum test was used for comparison of sensor accuracy for week 1 versus week 2. The data were analyzed in a generalized linear model to account for the …

Continuous glucose monitoring (CGM) has been demonstrated in randomized trials to improve glucose control in patients with type 1 diabetes (T1D) (1–3); however, most of the participants in these trials have used a pump for insulin delivery, and the use of CGM in T1D patients receiving insulin by injection has not been well studied. We used the T1D Exchange registry database to assess the impact of CGM on HbA1c in insulin injection users. Details on the informed consent process, eligibility criteria, and data collection methods have been previously published (4). Participants were defined as CGM users if CGM was used for real-time diabetes management during the 30 days prior to the clinic visit. Among the 17,731 registry participants with T1D duration >1 year who had a clinic visit between June 2014 and October 2015, 6,222 (35%) used injections alone, 8,783 (50%) used pump alone, 2,316 (13%) used pump with CGM, and 410 (2%) used injections with CGM. A Dexcom CGM was being used by …

Diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN) share common pathological mechanisms and are favorably impacted by intensive glycemic control. American Indians have disproportionately higher rates of type 2 diabetes (T2D), younger age of diabetes onset, and earlier development of long-term complications than other ethnic groups (1). Diabetes as an underlying cause of death is 2.5–3.5 times higher among American Indians than whites, yet the DPN burden among American Indians has not been systematically evaluated. We assessed DPN prevalence in Pima Indians and evaluated the relationship between DPN and DN. A total of 79 Pima Indians with T2D (age 53 ± 11 years, diabetes duration 25 ± 6 years, 73% female, and mean HbA1c 9.5 ± 1.9% [80 ± 7 mmol/mol]) from the Gila River community were enrolled. DPN status was ascertained using the Michigan Neuropathy Screening Instrument (MNSI) …

Sleep restriction is associated with insulin resistance and an increased risk for type 2 diabetes (1–3). Here, we investigated whether only 2 nights of recovery sleep, as may occur on weekends, reverses the negative effects of short-term sleep restriction on glucose homeostasis. Nineteen healthy young lean men were studied under controlled laboratory conditions during normal sleep and sleep restriction in a randomized order, as previously reported (1,2,4). The institutional review board of The University of Chicago approved the protocol, and all participants gave written informed consent. During normal sleep, participants were allowed 8.5 h in bed (2300–0700) for 4 consecutive nights. During sleep restriction, participants were allowed 4.5 h in bed (0100–0530) for 4 consecutive nights, immediately followed by recovery sleep for 2 consecutive nights with 12 h in bed on the first night (2200–1000) and 10 h in bed on the second night (2200–0800). A frequently sampled intravenous glucose tolerance test (ivGTT) was performed at 1000 after 4 nights of normal sleep, 4 nights of sleep restriction, and 2 nights …

High hemoglobin A1c (A1C) levels are associated with poor clinical outcomes in hospitalized patients. Recent guidelines have recommended performing A1C measurements in hospitalized patients with hyperglycemia to differentiate between stress hyperglycemia and undiagnosed diabetes, to assess the level of glycemic control prior to admission in patients with diabetes, and to tailor appropriate diabetes therapy regimens at hospital discharge (1). To study the predictive role of admission A1C on inpatient glycemic control in medical and surgical hospitalized patients with type 2 diabetes, we combined inpatient data from four randomized controlled trials of patients treated with a basal-bolus insulin regimen (2–5). We adopted the definition of optimal glycemic control as a combination of blood glucose (BG) levels below 180 mg/dL without hypoglycemia (BG

Islet transplantation is an experimental therapy for type 1 diabetes. Though it is increasingly successful, limitations include unpredictable declines in islet graft function (1). There is still inadequate knowledge of specific human islet characteristics that predispose to successful and durable islet graft function and what types of donors are more likely to have islets with these beneficial traits. The relationship between the composition of dissociated human islets (as opposed to whole islets) and transplant outcomes has been studied (2), with a positive association between recipients’ acute insulin response to glucose (AIRg) posttransplant and number of pancreatic ductal cells in the preparation (a positive association with number of β-cells approached significance). However, as dissociation inherently damages islets, β-cells enumerated after dissociation may no longer reflect the number of β-cells within whole islets ultimately transplanted. Using an epidemiological approach, we therefore investigated 1 ) the independent association of the β-cell composition of transplanted whole human islets with recipient outcomes and 2 ) the donor …

Diabetic foot ulcers have a biomechanical etiology related to triaxial plantar stresses (3DS) (1). Bergtholdt and Brand (2) suggested that the foot would heat up before breaking down, indicating that elevated 3DS in the diabetic foot would result in inflammation that could be monitored by thermography. The purpose of this study was to explore the hypothesized relationship between 3DS and plantar temperatures. Twenty-eight individuals with diabetes, 14 with peripheral neuropathy (DN) and 14 without (DC), walked at self-selected speeds across a custom-built plate that quantified 3DS. After 10 min of acclimation, resting barefoot temperatures were recorded using a Fluke infrared thermal camera. Linear regressions were used to reveal associations between magnitudes of 3DS and resting temperatures. Associations between locations of peak 3DS and peak temperatures were also examined. As assessed by linear regression, temperature was a statistically significant predictor of peak shear stress (PS) and shear-time integral magnitudes at the hallux. No significant association was found …

Acetaminophen (paracetamol) interferes with continuous glucose monitor (CGM) sensing, resulting in falsely elevated CGM glucose values in both sensors currently approved by the U.S. Food and Drug Administration (FDA). In amperometric glucose biosensors, particularly those measuring hydrogen peroxide, acetaminophen’s phenolic moiety is oxidized at the sensing electrode, producing an electrochemical signal not related to glucose (1). Limited published data exist documenting the magnitude of the effect of acetaminophen on CGM glucose (2), especially in the outpatient setting with contemporary sensor technology. Currently, the FDA recommends that insulin dosing decisions are based on blood glucose (BG) meter values, not CGM glucose values. Given the common use of acetaminophen, its interference with CGM sensing has significant clinical implications for patients who use CGM. To better understand this effect, we performed an acetaminophen challenge as part of an outpatient study designed to investigate the potential challenges to closed-loop systems, which use CGM sensor …

Repeated delivery of insulin in the same location induces a local reaction in the subcutaneous adipose tissue, often leading to lipohypertrophy (1,2). Advanced lipohypertrophy leads to slower, erratic insulin absorption due to the fibrous, relatively avascular nature of the tissue (3). Although lipohypertrophied tissue is commonly used for continuous glucose monitoring (CGM) sensor sites, the effect on sensor performance is unknown. Therefore, we analyzed the accuracy of sensors used simultaneously in lipohypertrophied and normal tissue. In this prospective, multicenter study, subjects with type 1 diabetes and lipohypertrophy (≥3 cm diameter) were instructed to wear two Dexcom G4 Platinum sensors simultaneously: one in lipohypertrophied tissue and the second in normal tissue for 2 consecutive weeks. This procedure was then repeated on each subject with new sensors being worn simultaneously for a second 2-week period. Blood glucose (BG) readings from Bayer CONTOUR NEXT meters served as reference (4), with absolute …

Studies using outpatient closed-loop insulin delivery for type 1 diabetes have recently been published (1–5). We conducted a 5-day outpatient feasibility study comparing hybrid closed-loop (HCL) to sensor-augmented pump therapy with low-glucose suspend (SAPT + LGS) in eight patients with type 1 diabetes using an open-label randomized crossover trial design (ACTRN12614001005640). We used the Medtronic HCL system: MiniMed insulin pump, MiniMed Enlite II glucose sensor, MiniMed MiniLink REAL-time sensor, MiniMed Translator, and an Android mobile device with the algorithm (proportional integrative derivate with insulin feedback and additional safety parameters—primarily being an upper limit of allowable insulin delivery). Multiple algorithm parameters were individualized according to total daily insulin requirements in the preceding 48 h. Meals were announced by entering a capillary glucose value and meal carbohydrate content, for which bolus insulin was delivered according to the patient’s unique carbohydrate ratio. The Android mobile device sent data via the Internet, …

Postprandial hyperglycemia is an important therapeutic target for optimizing glycemic control and for mitigating the proatherogenic vascular environment characteristic of type 2 diabetes. Existing evidence indicates that the quantity and type of carbohydrate consumed influence blood glucose levels and that the total amount of carbohydrate consumed is the primary predictor of glycemic response (1). Previous studies have shown that premeal ingestion of whey protein, as well as altering the macronutrient composition of a meal, reduces postmeal glucose levels (2–4). There are limited data, however, regarding the effect of food order on postprandial glycemia in patients with type 2 diabetes (5). In this pilot study, we sought to examine the effect of food order, using a typical Western meal, incorporating vegetables, protein, and carbohydrate, on postprandial glucose and insulin excursions in overweight/obese adults with type 2 diabetes. A total of 11 subjects (6 female, 5 male) with metformin-treated type 2 diabetes were studied …

Approximately 50% of patients with diabetes (DM) will eventually develop neuropathy. Large-scale studies have demonstrated that the regulation of blood glucose levels aids in the prevention and progression of diabetic peripheral neuropathy (DPN), but glycemic control does not impact established neuropathy or its severity (1). Causative factors also include microvascular insufficiency, defective neurotrophism, abnormal lipid metabolism, and oxidative and nitrosative stress (2). A key component of nitrosative stress, nitrotyrosine (NT), has multiple cytotoxic effects. Accumulation of NT has been identified in several neural structures in both rodents and humans (3), reflected by raised NT concentrations in the plasma of subjects with DM (4). The aim of this study was to evaluate the relationship between NT concentrations with the presence and severity of possible/probable (PP-DM-DPN) and established (DM-DPN) neuropathy in subjects with DM compared with healthy control subjects …

The prevalence of latent autoimmune diabetes in adults (LADA) in patients diagnosed with type 2 diabetes mellitus (T2DM) ranges from 7 to 10% (1). They present at a younger age and have a lower BMI but poorer glycemic control, which may increase the risk of complications (2). However, a recent analysis of the Collaborative Atorvastatin Diabetes Study (CARDS) has demonstrated no difference in macrovascular or microvascular events between patients with LADA and T2DM, but neuropathy was not assessed (3). Previous studies quantifying neuropathy in patients with LADA are limited. In this study, we aimed to accurately quantify neuropathy in subjects with LADA compared with matched patients with T2DM.