Albuminuria According to Status of Autoimmunity and Insulin Sensitivity Among Youth With Type 1 and Type 2 Diabetes

OBJECTIVE

To evaluate whether etiologic diabetes type is associated with the degree of albuminuria in children with diabetes.

RESEARCH DESIGN AND METHODS

SEARCH is an observational, longitudinal study of children with diabetes. Youth with newly diagnosed diabetes were classified according to diabetes autoantibody (DAA) status and presence of insulin resistance. We defined insulin resistance as an insulin sensitivity score <25th percentile for the United States general youth population. DAA status was based on positivity for the 65-kD isoform of glutamate decarboxylase and insulinoma-associated protein 2 antigens. The four etiologic diabetes type groups were as follows: DAA⁺/insulin-sensitive (IS) (n = 1,351); DAA⁺/insulin-resistant (IR) (n = 438); DAA⁻/IR (n = 379); and DAA⁻/IS (n = 233). Urinary albumin:creatinine ratio (UACR) was measured from a random urine specimen. Multivariable regression analyses assessed the independent relationship between the four diabetes type groups and magnitude of UACR.

RESULTS

Adjusted UACR means across the four groups were as follows: DAA⁺/IS = 154 μg/mg; DAA⁺/IR = 137 μg/mg; DAA⁻/IR = 257 μg/mg; and DAA⁻/IS = 131 μg/mg (P < 0.005). Only DAA⁻/IR was significantly different. We performed post hoc multivariable regression analysis restricted to the two IR groups to explore the contribution of DAA status and insulin sensitivity (continuous) to the difference in UACR between the IR groups. Only insulin sensitivity was significantly associated with UACR (β = −0.54; P < 0.0001).

CONCLUSIONS

In youth with diabetes, the DAA⁻/IR group had a greater UACR than all other groups, possibly because of the greater magnitude of insulin resistance. Further exploration of the relationships between severity of insulin resistance, autoimmunity, and albuminuria in youth with diabetes is warranted.Previous reports suggested that the clinical course and factors contributing to the development and progression of diabetic nephropathy did not differ by diabetes type and that diabetic nephropathy was preceded by albuminuria that worsened over time (1,2). More recent data have further elucidated the natural history of diabetic kidney disease. In the absence of albuminuria, a significant number of people with diabetes, especially type 2, still develop a decline in glomerular filtration rate (3,4). Thus, there may be identifiable differences in the natural history of nephropathy inherent to the underlying diabetes type. Multiple pediatric diabetes cohorts have found a higher prevalence of albuminuria and progressive kidney failure in youth with a clinical diagnosis of type 2 diabetes than with type 1 diabetes (5–7). Such data suggest that insulin resistance, a key component of the pathophysiology of type 2 diabetes, may be an important contributor to diabetic nephropathy in youth with diabetes.The epidemic of overweight and obesity has made it increasingly difficult to clinically diagnose diabetes type, because insulin resistance and autoimmunity often coexist (8,9). Cohort studies of youth with type 1 diabetes have found a significant increase in microvascular and macrovascular diseases in those with concurrent insulin resistance (10–12). The prevalence of albuminuria in insulin-resistant (IR) individuals with type 1 diabetes has not been compared with individuals with type 2 diabetes. Thus, the role of autoimmunity and insulin resistance across the spectrum of diabetes types and the risk for microvascular complications warrant investigation. Herein, we investigate the magnitude of albuminuria according to the status of autoimmunity and insulin resistance in youth with newly diagnosed type 1 and type 2 diabetes.     

Diabetes Genetic Predisposition Score and Cardiovascular Complications Among Patients With Type 2 Diabetes

OBJECTIVE

To examine the association between genetic predisposition to type 2 diabetes (T2D) and risk of cardiovascular disease (CVD) among patients with T2D.

RESEARCH DESIGN AND METHODS

The current study included 1,012 men and 1,310 women with T2D from the Health Professionals Follow-up Study and Nurses’ Health Study, including 677 patients with CVD and 1,645 non-CVD control subjects. A genetic predisposition score (GPS) was calculated on the basis of 36 established independent diabetes-predisposing variants.

RESULTS

Each additional diabetes-risk allele in the GPS was associated with a 3% increased risk of CVD (odds ratio [OR] 1.03 [95% CI 1.00–1.06]). The OR was 1.47 (1.11–1.95) for CVD risk by comparing extreme quartiles of the GPS (P for trend = 0.01). We also found that the GPS was positively associated with hemoglobin A_1c levels (P = 0.009).

CONCLUSIONS

Genetic predisposition to T2D is associated with an increased risk of cardiovascular complications in patients with T2D.It has been postulated that type 2 diabetes (T2D) and cardiovascular disease (CVD) might spring from a “common soil” where both conditions share common genetic and environmental antecedents (1). Identification of the shared genetic risk factors may improve our understanding of the etiological link of these two diseases. A recent study reported a significant association between a genetic score based on multiple diabetes-predisposing variants and increased risk of coronary heart disease (CHD) in a general population (2). In this study, we constructed a genetic predisposition score (GPS) on the basis of 36 established T2D-predisposing variants, and examined its association with cardiovascular complications among people with T2D.     

Racial and Ethnic Differences in an Estimated Measure of Insulin Resistance Among Individuals With Type 1 Diabetes

OBJECTIVE

Insulin resistance is greater in racial/ethnic minorities than in non-Hispanic whites (NHWs) for those with and without type 2 diabetes. Because previous research on insulin resistance in type 1 diabetes was limited to NHWs, racial/ethnic variation in an estimated measure of insulin resistance in type 1 diabetes was determined.

RESEARCH DESIGN AND METHODS

The sample included 79 individuals with type 1 diabetes diagnosed at age <18 years (32.9% NHWs, 46.8% non-Hispanic black [NHB], 7.6% other/mixed, and 12.7% Hispanic) and their families. Estimated glucose disposal rate (eGDR) (milligrams per kilogram per minute; a lower eGDR indicates greater insulin resistance) was calculated using A1C, waist circumference, and hypertension status.

RESULTS

Mean current age was 13.5 years (range 3.2–32.5) and diabetes duration was 5.7 years (0.1–19.9). eGDR was inversely associated with age. Compared with that in NHWs, age-adjusted eGDR was significantly lower among nonwhites (NHB, other/mixed, and Hispanic: Δ = −1.83, P = 0.0006). Age-adjusted eGDR was negatively associated with body fat, triglycerides, urinary albumin/creatinine, acanthosis nigricans, parental obesity, and parental insulin resistance and positively related to HDL and sex hormone–binding globulin. In multivariable analysis, lower eGDR was significantly associated with older age, nonwhite race/ethnicity, acanthosis, and lower HDL.

CONCLUSIONS

Minorities with type 1 diabetes are significantly more insulin resistant, as measured by eGDR, than NHWs. Exploring potential mechanisms, including disparities in care and/or physiological variation, may contribute to preventing racial/ethnic differences in insulin resistance–associated outcomes.Insulin resistance is common in type 2 diabetes (1) and seems to play a role in the natural history (2) and risk of complications (3) in type 1 diabetes as well. Measurement of insulin resistance in type 1 diabetes is difficult because methods used in nondiabetic and type 2 individuals, e.g., insulin or homeostasis model assessment (4), cannot be used in hypoinsulinemia. The euglycemic-hyperinsulinemic clamp has been used; however, it is labor-intensive and invasive and therefore is not suitable for population-based studies. In response, a derived measure of insulin resistance, the estimated glucose disposal rate (eGDR), has been developed using clinical measures and is strongly correlated with clamp-measured insulin resistance (5).Consistent with clamp studies in type 1 diabetes (2), lower eGDR is associated with older age (6), longer duration of diabetes (6), greater adiposity (6), family history of type 2 diabetes (5), poor glycemic control (5), and elevated lipids (6). Low eGDR predicts incident retinopathy (3), nephropathy (3,6), neuropathy (7), and cardiovascular disease in type 1 diabetes (3,6). These findings are primarily based on non-Hispanic white (NHW) adults.Previous research shows racial/ethnic differences in insulin resistance for healthy individuals and those with type 2 diabetes. For example, minority adults with and without type 2 diabetes were more insulin resistant than their NHW counterparts (1,8). Similarly, in nondiabetic youth, minorities were more insulin resistant than NHWs (9,10). Despite these findings, to our knowledge, there are no data on insulin resistance in minorities with type 1 diabetes.Therefore, we sought to determine 1) whether racial/ethnic differences in insulin resistance, as measured by eGDR, exist in type 1 diabetes and 2) whether the association of eGDR with factors traditionally related to insulin resistance differed by race/ethnicity. It was hypothesized that insulin resistance is greater in minorities than in whites and that associations with insulin resistance are consistent across race/ethnicity.     

Obstructive Sleep Apnea Among Obese Patients With Type 2 Diabetes

OBJECTIVE

To assess the risk factors for the presence and severity of obstructive sleep apnea (OSA) among obese patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Unattended polysomnography was performed in 306 participants.

RESULTS

Over 86% of participants had OSA with an apnea-hypopnea index (AHI) ≥5 events/h. The mean AHI was 20.5 ± 16.8 events/h. A total of 30.5% of the participants had moderate OSA (15 ≤ AHI <30), and 22.6% had severe OSA (AHI ≥30). Waist circumference (odds ratio 1.1; 95% CI 1.0–1.1; P = 0.03) was significantly related to the presence of OSA. Severe OSA was most likely in individuals with a higher BMI (odds ratio 1.1; 95% CI 1.0–1.2; P = 0.03).

CONCLUSIONS

Physicians should be particularly cognizant of the likelihood of OSA in obese patients with type 2 diabetes, especially among individuals with higher waist circumference and BMI.We report the prevalence of obstructive sleep apnea (OSA) and the factors that increase the risk and severity of OSA among 306 obese patients with type 2 diabetes enrolled in Sleep AHEAD, a four-site ancillary study of the Look AHEAD Trial (Action for Health in Diabetes).     

Oral Insulin: A Comparison With Subcutaneous Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation compared with subcutaneously injected regular human insulin (RHI).

RESEARCH DESIGN AND METHODS

Ten male patients with type 2 diabetes (means ± SD; A1C 7.0 ± 1.1%; BMI 28.3 ± 2.7 kg/m²) received either 300 units of insulin combined with 400 mg of delivery agent orally or 15 units RHI subcutaneously under isoglycemic clamp conditions.

RESULTS

Maximum insulin concentration was greater and onset of action was faster with OI (C_max 93 ± 71 vs. 33 ± 11 μU/ml; AUC_GIR^(0−1h) 173 ± 86 vs. 27 ± 32 mg/kg; P < 0.05). Mean insulin concentration and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7 ± 4% (1st 2 h).

CONCLUSIONS

This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action but also shows a rather high between-subject variability in absorption.Oral administration of insulin has the potential advantage of a more physiological action by its direct effect on hepatic glucose production (1,2). Thus far various oral insulin approaches however have only partially produced satisfactory results (1,3,4). Gastrointestinal absorption of insulin is hampered by factors such as enzymatic degradation and lack of permeation through epithelial cells (5). Noncovalent interaction of the novel drug-carrier molecule monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) with insulin might create more favorable physico-chemical properties for gastrointestinal insulin absorption (6,7). In this study, 4-CNAB has been combined with human insulin to facilitate gastrointestinal insulin absorption.     

HDL Cholesterol and Cancer Risk Among Patients With Type 2 Diabetes

OBJECTIVETo investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients.RESULTSDuring a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30–39.9, 40–49.9, 50–59.9, 60–69.9, 70–79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (P_trend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (P_trend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up.CONCLUSIONSThe study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation.     

Cost-effectiveness of Insulin Degludec Versus Insulin Glargine in Insulin-naive Chinese Patients With Type 2 Diabetes

Purpose

The goal of this study was to investigate the long-term economic outcomes of insulin degludec versus insulin glargine use in Chinese patients with type 2 diabetes mellitus (T2DM) whose oral antidiabetic drugs did not provide sufficient glycemic control.

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Effect of Internet Therapeutic Intervention on A1C Levels in Patients With Type 2 Diabetes Treated With Insulin

OBJECTIVE

To assess the effect of an Internet-based glucose monitoring system (IBGMS) on A1C levels in patients with type 2 diabetes treated with insulin.

RESEARCH DESIGN AND METHODS

This trial involved 50 patients randomly assigned to receive either conventional treatment alone or with additional follow-up through an IBGMS for 6 months. Patients randomized to the intervention group uploaded blood glucose readings every 2 weeks to a secure Web site for review and receipt of feedback from their endocrinologist. A1C and laboratory test results were collected at 0, 3, and 6 months.

RESULTS

The baseline parameters were not significantly different. Over a 6-month follow-up, A1C dropped from 8.8 to 7.6% (P < 0.001) in the intervention group compared with 8.5 to 8.4% (P = 0.51) in the control group.

CONCLUSIONS

The use of IBGMS significantly improved A1C levels in patients with type 2 diabetes treated with insulin.In the management of diabetes, self-monitoring of blood glucose (SMBG) is performed as an adjunct to A1C measurements in order to assess and modify treatment (1–3); however, it often requires healthcare professionals to help interpret the results to refine treatment (4–6). The Internet provides a readily accessible platform for communication and remote health monitoring (7). In this study, we evaluated whether the use of an IBGMS would improve the outcome of treatment for patients with type 2 diabetes.     

Missed Insulin Boluses for Snacks in Youth With Type 1 Diabetes

OBJECTIVE

To evaluate the effects of missed insulin boluses for snacks in youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Three months of simultaneous continuous subcutaneous insulin infusion and continuous glucose monitoring data from nine subjects were retrospectively evaluated. Glucose excursions between 1330 and 1700 h were defined as relating to snacks with insulin or snacks with no insulin administered. Area under the curve >180 mg/dl (AUC >180), average Δ glucose, and rate of change were analyzed and compared within and between groups.

RESULTS

A total of 94 snacks without insulin and 101 snacks with insulin were analyzed. Snacks without insulin had significantly higher log (AUC >180 + 1) (1.26 vs. 0.44 mg/dl per event; P < 0.001), Δ glucose (114 vs. 52 mg/dl; P < 0.001), and average rate of change (1.3 vs. 1.1 mg/dl per minute; P < 0.001).

CONCLUSIONS

This study shows that afternoon snacks without insulin boluses are common and result in significantly higher glucose excursions than snacks with insulin administration.Previous studies have demonstrated the deleterious effect of missed insulin doses for meals (1–4). None, however, have examined the effect of missed insulin boluses for snacks. Because youth frequently snack when unsupervised, it is likely that missed insulin boluses are even more common for snacks than for meals. The purpose of this investigation was to use data from continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) together to evaluate the glycemic profiles of missed insulin boluses for afternoon snacks.     

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes

OBJECTIVEEmerging data from animal and human pilot studies suggest potential benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA) on lung function. We aimed to assess the association of GLP-1RA and chronic lower respiratory disease (CLRD) exacerbation in a population with comorbid type 2 diabetes (T2D) and CLRD.RESEARCH DESIGN AND METHODSA new-user active-comparator analysis was conducted with use of a national claims database of beneficiaries with employer-sponsored health insurance spanning 2005–2017. We included adults with T2D and CLRD who initiated GLP-1RA or dipeptidyl peptidase 4 inhibitors (DPP-4I) as an add-on therapy to their antidiabetes regimen. The primary outcome was time to first hospital admission for CLRD. The secondary outcome was a count of any CLRD exacerbation associated with an inpatient or outpatient visit. We estimated incidence rates using inverse probability of treatment weighting for each study group and compared via risk ratios.RESULTSThe study sample consisted of 4,150 GLP-1RA and 12,540 DPP-4I new users with comorbid T2D and CLRD. The adjusted incidence rate of first CLRD admission during follow-up was 10.7 and 20.3 per 1,000 person-years for GLP-1RA and DPP-4I users, respectively, resulting in an adjusted hazard ratio of 0.52 (95% CI 0.32–0.85). For the secondary outcome, the adjusted incidence rate ratio was 0.70 (95% CI 0.57–0.87).CONCLUSIONSGLP-1RA users had fewer CLRD exacerbations in comparison with DPP-4I users. Considering both plausible mechanistic pathways and this real-world evidence, potential beneficial effects of GLP-1RA may be considered in selection of an antidiabetes treatment regimen. Randomized clinical trials are warranted to confirm our findings.     

Acute Metabolic Effects of Exenatide in Patients With Type 1 Diabetes With and Without Residual Insulin to Oral and Intravenous Glucose Challenges

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood.

RESEARCH DESIGN AND METHODS

Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads.

RESULTS

During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration.

CONCLUSIONS

Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.     

Increased CD36 Expression Signals Monocyte Activation Among Patients With Type 2 Diabetes

OBJECTIVE

To explore the hypothesis that CD36, a scavenger receptor and fatty acid translocase, is upregulated in peripheral blood mononuclear cells (PBMCs) among patients with type 2 diabetes and is a biomarker of PBMC activation and inflammation.

RESEARCH DESIGN AND METHODS

We used a cross-sectional observational design to study a multi-racial/ethnic population sample consisting of Caucasians, Hispanics, and Native Americans with type 2 diabetes (n = 33) and nondiabetic control subjects (n = 27). PBMC CD36 mRNA/protein and plasma high sensitivity (hs) C-reactive protein (hsCRP), hs–interleukin-6 (hsIL-6), and adiponectin were measured.

RESULTS

Unadjusted PBMC CD36 mRNA and protein were 1.56- and 1.63-fold higher, respectively, among type 2 diabetic subjects versus control subjects. PBMC CD36 protein was directly associated with CD36 mRNA, plasma hsCRP, and hsIL-6 and inversely associated with plasma adiponectin in both groups.

CONCLUSIONS

Increased CD36 expression is a biomarker of PBMC activation and inflammation and may become a useful tool in cardiovascular disease risk stratification.The prevalence of type 2 diabetes is increasing in epidemic proportions among minority populations. Cardiovascular disease (CVD) is a major cause of morbidity and mortality among diabetic patients. New methods for risk stratification are needed to reduce the burden of CVD among patients with diabetes.CD36, a 88-kDa transmembrane glycoprotein and a cell surface scavenger receptor for oxidized low-density lipoproteins (oxLDL), plays a critical role in the pathogenesis of atherosclerosis and CVD (1,2). Ligation of oxLDL by CD36 in macrophages induces activation of nuclear factor κ–light-chain enhancer of activated B-cells (NFκB) and production of proinflammatory cytokines, e.g., tumor necrosis factor α/β (TNF-α/β), interleukin (IL)-1β, IL-6, and interferon β/γ. Production of proinflammatory cytokines is reduced in CD36-deficient macrophages (2). The size of atherosclerotic lesions is reduced by inactivation of CD36 and increased by reintroduction of CD36 in apolipoprotein E/CD36-deficient mice. CD36 expression is increased in the presence of high glucose concentrations. Therefore, assessment of CD36 levels may become a valuable tool in CVD risk stratification among patients with type 2 diabetes.The majority of previous clinical studies of CD36 expression have been conducted in a single racial/ethnic group. In contrast, the present study explored the hypothesis that there is coordinated upregulation of peripheral blood mononuclear cell (PBMC) CD36 mRNA and protein, signaling PBMC activation and increased production of proinflammatory cytokines among non-Hispanic whites, Hispanics, and American Indians with type 2 diabetes.     

Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes

OBJECTIVE

To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a 24-week open-label, multicenter study, 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 μg) or a titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving <50 units/day basal insulin for <6 months. The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) ≥70–<100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The proportion of patients achieving A1C ≤7.0% without weight gain or severe hypoglycemia at week 24 was the primary end point.

RESULTS

More pramlintide- than RAIA-treated patients achieved the primary end point (30 vs. 11%, P = 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded similar mean ± SEM values for FPG and A1C at 24 weeks (122 ± 7 vs. 123 ± 5 mg/dl and 7.2 ± 0.2 vs. 7.0 ± 0.1%, respectively) and similar least squares mean reductions from baseline to end point (−31 ± 6 vs. −34 ± 6 mg/dl and −1.1 ± 0.2 vs. −1.3 ± 0.2%, respectively). RAIAs but not pramlintide caused weight gain (+4.7 ± 0.7 vs. +0.0 ± 0.7 kg, P < 0.0001). Fewer patients reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group.

CONCLUSIONS

In patients taking basal insulin and OADs, premeal fixed-dose pramlintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen sometimes caused nausea but no weight gain and less hypoglycemia.Adding basal insulin therapy to oral agents improves glycemic control for many patients with type 2 diabetes, but up to 50% of patients continue to have A1C values >7% (1,2,3,4,5). Persistent after-meal hyperglycemia is generally observed in such patients (6). The usual next step in treatment is addition of mealtime insulin injections, but this approach increases risks of weight gain and hypoglycemia (4,6).Previous studies have shown that defects in addition to insulin deficiency contribute to after-meal hyperglycemia. Both insulin and amylin are secreted by β-cells, and, in individuals with abnormal β-cell function, glucose- and mixed meal–stimulated secretion of both hormones is delayed and reduced (7,8,9). Insulin deficiency impairs suppression of hepatic glucose production and enhancement of glucose uptake by tissues that normally limit postmeal hyperglycemia. Amylin deficiency accelerates gastric emptying, increases glucagon secretion, and alters satiety mechanisms (10,11).Pramlintide, an injectable synthetic analog of amylin, slows gastric emptying, attenuates postprandial glucagon secretion, enhances satiety, and reduces food intake (12,13,14). Pramlintide is approved as adjunctive treatment for patients with diabetes who use mealtime insulin with or without oral antihyperglycemic drugs (OADs) and have not achieved desired glucose control. Recently, a 16-week, double-blind, placebo-controlled study of patients with type 2 diabetes showed that pramlintide reduces A1C and weight without increasing insulin-induced hypoglycemia when added to basal insulin ± OADs without mealtime insulin (15).Pramlintide may offer an additional therapeutic option for mealtime use by patients with type 2 diabetes already using basal insulin. Rapid-acting insulin analogs (RAIAs) and pramlintide have different mechanisms of action and different patterns of desired and unwanted effects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight gain and hypoglycemia (6), whereas pramlintide is associated with weight loss and nausea (15,16). This study was designed to compare the efficacy and side effects of pramlintide versus RAIAs when added to basal insulin to intensify treatment of type 2 diabetes.     

Sudden Cardiac Death in Patients With Type 1 Versus Type 2 Diabetes

ObjectiveTo investigate the association between type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) with risk of sudden cardiac arrest (SCA).MethodsIn a prospective community-based study of SCA from February 1, 2002, through November 30, 2019, we ascertained 2771 cases age 18 years of age or older and matched them to 8313 controls based on geography, age, sex, and race/ethnicity. We used logistic regression to evaluate the independent association between diabetes, T1D, T2D, and SCA.ResultsPatients had a mean age of 64.5±15.9 years, were 33.3% female and 23.9% non-White race. Overall, 36.7% (n=1016) of cases and 23.8% (n=1981) of controls had diabetes. Among individuals with diabetes, the proportion of T1D was 6.5% (n=66) among cases and 2.0% among controls (n=40). Diabetes was associated with 1.5-times higher odds of SCA. Compared with those without diabetes, the odds ratio and 95% CI for SCA was 4.36 (95% CI, 2.81 to 6.75; P<.001) in T1D and 1.45 (95% CI, 1.30 to 1.63; P<.001) in T2D after multivariable adjustment. Among those with diabetes, the odds of having SCA were 2.41 times higher in T1D than in T2D (95% CI, 1.53 to 3.80; P<.001). Cases of SCA with T1D were more likely to have an unwitnessed arrest, less likely to receive resuscitation, and less likely to survive compared with those with T2D.ConclusionType 1 diabetes was more strongly associated with SCA compared with T2D and had less favorable outcomes following resuscitation. Diabetes type could influence the approach to risk stratification and prevention of SCA.     

Driving Mishaps Among Individuals With Type 1 Diabetes: A prospective study

OBJECTIVE

Hypoglycemia-related neuroglycopenia disrupts cognitive-motor functioning, which can impact driving safety. Retrospective studies suggest that drivers with type 1 diabetes experience more collisions and citations than their nondiabetic spouses. We present the first prospective data documenting the occurrence of apparent neuroglycopenia-related driving performance impairments.

RESEARCH DESIGN AND METHODS

We completed the initial screening of 452 drivers from three geographically diverse centers who then reported monthly occurrences of driving “mishaps,” including collisions, citations, losing control, automatic driving, someone else taking over driving, and moderate or severe hypoglycemia while driving.

RESULTS

Over 12 months, 52% of the drivers reported at least one hypoglycemia-related driving mishap and 5% reported six or more. These mishaps were related to mileage driven, history of severe hypoglycemia, and use of insulin pump therapy.

CONCLUSIONS

Many individuals with type 1 diabetes report hypoglycemia-related driving events. Clinicians should explore the recent experiences with hypoglycemia while driving and the risk of future events.Hypoglycemia is the major barrier to type 1 diabetes intensive insulin therapy (1), in part because of its disruptions on cognitive-motor functioning (2). One practical implication is its adverse effect on vehicular driving performance, resulting in collisions and citations (3,4). These potential disruptive effects are made further problematic because some individuals with diabetes decide to drive when they know that their blood glucose is low (5).Retrospective studies (6) have documented that individuals with type 1 diabetes compared with those with type 2 diabetes have more collisions and citations. The current study presents the first prospective data documenting the occurrence of different types of hypoglycemia-related driving mishaps.