Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

Long-Term Outcomes of Medical Management vs Bariatric Surgery in Type 2 Diabetes.

Importance: Randomized clinical trials of bariatric surgery have been limited in size, type of surgical procedure, and follow-up duration. Objective: To determine long-term glycemic control and safety of bariatric surgery compared with medical/lifestyle management of type 2 diabetes. Design, Setting, and Participants: ARMMS-T2D (Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes) is a pooled analysis from 4 US single-center randomized trials conducted between May 2007 and August 2013, with observational follow-up through July 2022. Intervention: Participants were originally randomized to undergo either medical/lifestyle management or 1 of the following 3 bariatric surgical procedures: Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding. Main Outcome and Measures: The primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 7 years for all participants. Data are reported for up to 12 years. Results: A total of 262 of 305 eligible participants (86%) enrolled in long-term follow-up for this pooled analysis. The mean (SD) age of participants was 49.9 (8.3) years, mean (SD) body mass index was 36.4 (3.5), 68.3% were women, 31% were Black, and 67.2% were White. During follow-up, 25% of participants randomized to undergo medical/lifestyle management underwent bariatric surgery. The median follow-up was 11 years. At 7 years, HbA1c decreased by 0.2% (95% CI, -0.5% to 0.2%), from a baseline of 8.2%, in the medical/lifestyle group and by 1.6% (95% CI, -1.8% to -1.3%), from a baseline of 8.7%, in the bariatric surgery group. The between-group difference was -1.4% (95% CI, -1.8% to -1.0%; P < .001) at 7 years and -1.1% (95% CI, -1.7% to -0.5%; P = .002) at 12 years. Fewer antidiabetes medications were used in the bariatric surgery group. Diabetes remission was greater after bariatric surgery (6.2% in the medical/lifestyle group vs 18.2% in the bariatric surgery group; P = .02) at 7 years and at 12 years (0.0% in the medical/lifestyle group vs 12.7% in the bariatric surgery group; P < .001). There were 4 deaths (2.2%), 2 in each group, and no differences in major cardiovascular adverse events. Anemia, fractures, and gastrointestinal adverse events were more common after bariatric surgery. Conclusion and Relevance: After 7 to 12 years of follow-up, individuals originally randomized to undergo bariatric surgery compared with medical/lifestyle intervention had superior glycemic control with less diabetes medication use and higher rates of diabetes remission. Trial Registration: ClinicalTrials.gov Identifier: NCT02328599.

Continuous glucose monitoring in patients with post-bariatric hypoglycaemia reduces hypoglycaemia and glycaemic variability.

AIM: To determine whether continuous glucose monitoring (CGM) can reduce hypoglycaemia in patients with post-bariatric hypoglycaemia (PBH). MATERIALS AND METHODS: In an open-label, nonrandomized, pre-post design with sequential assignment, CGM data were collected in 22 individuals with PBH in two sequential phases: (i) masked (no access to sensor glucose or alarms); and (ii) unmasked (access to sensor glucose and alarms for low or rapidly declining sensor glucose). Twelve participants wore the Dexcom G4 device for a total of 28 days, while 10 wore the Dexcom G6 device for a total of 20 days. RESULTS: Participants with PBH spent a lower percentage of time in hypoglycaemia over 24 hours with unmasked versus masked CGM (<3.3 mM/L, or <60 mg/dL: median [median absolute deviation {MAD}] 0.7 [0.8]% vs. 1.4 [1.7]%, P = 0.03; <3.9 mM/L, or <70 mg/dL: median [MAD] 2.9 [2.5]% vs. 4.7 [4.8]%; P = 0.04), with similar trends overnight. Sensor glucose data from the unmasked phase showed a greater percentage of time spent between 3.9 and 10 mM/L (70-180 mg/dL) (median [MAD] 94.8 [3.9]% vs. 90.8 [5.2]%; P = 0.004) and lower glycaemic variability over 24 hours (median [MAD] mean amplitude of glycaemic excursion 4.1 [0.98] vs. 4.4 [0.99] mM/L; P = 0.04). During the day, participants also spent a greater percentage of time in normoglycaemia with unmasked CGM (median [MAD] 94.2 [4.8]% vs. 90.9 [6.2]%; P = 0.005), largely due to a reduction in hyperglycaemia (>10 mM/L, or 180 mg/dL: median [MAD] 1.9 [2.2]% vs. 3.9 [3.6]%; P = 0.02). CONCLUSIONS: Real-time CGM data and alarms are associated with reductions in low sensor glucose, elevated sensor glucose, and glycaemic variability. This suggests CGM allows patients to detect hyperglycaemic peaks and imminent hypoglycaemia, allowing dietary modification and self-treatment to reduce hypoglycaemia. The use of CGM devices may improve safety in PBH, particularly for patients with hypoglycaemia unawareness.

Hyperglycemia and hyperinsulinemia effects on anterior cingulate cortex myoinositol-relation to brain network functional connectivity in healthy adults.

Brain mechanisms underlying the association of diabetes metabolic disorders-hyperglycemia and insulin resistance-with cognitive impairment are unknown. Myoinositol is a brain metabolite involved in cell osmotic balance, membrane phospholipid turnover, and second messenger neurotransmission, which affect brain function. Increased brain myoinositol and altered functional connectivity have been found in diabetes, mild cognitive impairment, and Alzheimer's disease, but the independent effects of plasma glucose and insulin on brain myoinositol and function are not characterized. We measured myoinositol concentrations in the pregenual anterior cingulate cortex (ACC), a region involved in self-reflective awareness and decision making, using proton magnetic resonance spectroscopy, and whole brain resting-state functional connectivity using fMRI, during acute hyperglycemia (with attendant hyperinsulinemia) and euglycemic-hyperinsulinemia compared with basal fasting-euglycemia (EU) in 11 healthy nondiabetic participants (5 women/6 men, means ± SD, age: 27 ± 7 yr, fasting-glucose: 5.2 ± 0.4 mmol/L, fasting-insulin: 4.9 ± 4.4 µU/mL). Brain MR data were acquired during two separate visits: 1) EU followed by a 60-min hyperglycemic-clamp (glucose: 10.7 ± 0.2 mmol/L, insulin: 33 ± 6 µU/mL); 2) EU followed by a hyperinsulinemic-euglycemic-clamp (glucose: 5.3 ± 0.1 mmol/L, insulin: 27 ± 5 µU/mL) designed to match individual insulin levels achieved during the visit 1 hyperglycemic-clamp. Myoinositol decreased by 14% during the hyperglycemic-clamp (from 7.7 ± 1.5 mmol/kg to 6.6 ± 0.8 mmol/kg, P = 0.031), and by 9% during the hyperinsulinemic-euglycemic-clamp (from 7.1 ± 0.7 mmol/kg to 6.5 ± 0.7 mmol/kg, P = 0.014), with no significant difference between the two clamps. Lower myoinositol was associated with higher functional connectivity of the thalamus and precentral cortex with insula-ACC-related networks, suggesting myoinositol is involved in insulin modulation of cognitive/emotional network function in healthy adults. Regional brain myoinositol levels may be useful biomarkers for monitoring cognitive and mood-enhancing treatment responses.NEW & NOTEWORTHY Hyperinsulinemia-related decreases of brain anterior cingulate cortex (ACC) myoinositol independent of plasma glucose levels and the association of low ACC myoinositol with increased functional connectivity between sensorimotor regions and ACC/insula-related networks suggest involvement of myoinositol in insulin-modulated brain network function in healthy adults. In diabetes, elevated brain myoinositol may be due to reduced brain insulin levels or action, rather than hyperglycemia, and may be involved in brain network dysfunctions leading to cognitive or mood disorders.

Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D): Study rationale, design, and methods.

AIMS: Long-term data from randomized clinical trials comparing metabolic (bariatric) surgery versus a medical/lifestyle intervention for treatment of patients with obesity/overweight and type 2 diabetes (T2D) are lacking. The Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) is a consortium of four randomized trials designed to compare long-term efficacy and safety of surgery versus medical/lifestyle therapy on diabetes control and clinical outcomes. MATERIALS AND METHODS: Patients with T2D and body mass index (BMI) of 27-45 kg/m2 who were previously randomized to metabolic surgery (Roux-en-Y gastric bypass, adjustable gastric band, or sleeve gastrectomy) versus medical/lifestyle intervention in the STAMPEDE, SLIMM-T2D, TRIABETES, or CROSSROADS trials have been enrolled in ARMMS-T2D for observational follow-up. The primary outcome is change in glycated haemoglobin after a minimum 7 years of follow-up, with additional analyses to determine rates of diabetes remission and relapse, as well as cardiovascular and renal endpoints. RESULTS: In total, 302 patients (192 surgical, 110 medical/lifestyle) previously randomized in the four parent studies were eligible for participation in the ARMMS-T2D observational study. Participant demographics were 71% white, 27% African-American and 68% female. At baseline: age, 50 ± 8 years; BMI, 36.5 ± 3.5 kg/m2 ; duration of diabetes, 8.8 ± 5.6 years; glycated haemoglobin, 8.6% ± 1.6%; and fasting glucose, 168 ± 64 mg/dl. More than 35% of patients had a BMI <35 kg/m2 . CONCLUSIONS: ARMMS-T2D will provide the largest body of long-term, level 1 evidence to inform clinical decision-making regarding the comparative durability, efficacy and safety of metabolic surgery relative to a medical/lifestyle intervention among patients with T2D, including those with milder class I obesity or mere overweight.

Outreach Method Predicts Patient Re-engagement in Diabetes Care During Sustained Care Disruption.

OBJECTIVE: During the COVID-19 pandemic, visits for diabetes care were abruptly canceled without predefined procedures to re-engage patients. This study was designed to determine how outreach influences patients to maintain diabetes care and identify factors that might impact the intervention's efficacy. METHODS: A diabetes nursing team attempted outreach for patients who had a canceled appointment for diabetes between March 16, 2020, and June 19, 2020. Outreach status was defined as reached, message left, or no contact. Outcomes were defined as follows: (1) booking and (2) keeping a follow-up appointment. RESULTS: Seven hundred eighty-seven patients were included (384 [49%] were reached, 152 (19%) were left a message, and 251 (32%) had no contact). Reached patients were more likely to book [odds ratio (OR) = 2.43, P < .001] and keep an appointment (OR = 2.39, P < .001) than no-contact patients. Leaving a message did not increase the odds of booking (OR = 1.05, P = .84) or keeping (OR = 1.17, P = .568) an appointment compared with no contact. Older age was a significant predictor of booking an appointment (OR = 1.014 for each year of age, P = .037). Patients on insulin were more likely to keep their appointment (OR = 1.70, P = .008). Patients with a higher hemoglobin A1C level were less likely to keep their appointment (OR = 0.87 for each 1.0% increase in the hemoglobin A1C level, P = .011). CONCLUSION: These findings suggest that to optimize re-engagement during care disruption, 1-way communication is no better than no contact and that 2-way communication increases the likelihood that patients will maintain access to care. In addition, although higher-risk patients (eg, patients with older age or those on insulin) may be more incentivized to stay engaged, targeted outreach is needed for those with chronically poor glycemic control.

Efficacy and safety of dual add-on therapy with dapagliflozin plus saxagliptin versus glimepiride in patients with poorly controlled type 2 diabetes on a stable dose of metformin: Results from a 52-week, randomized, active-controlled trial.

AIMS: To evaluate the efficacy and safety of dapagliflozin (DAPA) + saxagliptin (SAXA) compared with glimepiride (GLIM) in patients with type 2 diabetes who were inadequately controlled [glycated haemoglobin (HbA1c) 7.5-10.5% (58-91 mmol/mol)] on metformin monotherapy. MATERIALS AND METHODS: This 52-week, multicentre, double-blind, active-controlled study (NCT02419612) randomized (1:1) patients on metformin to add-on DAPA 10 mg + SAXA 5 mg (n = 227) or GLIM 1-6 mg (titrated; n = 217). The primary efficacy endpoint was change in HbA1c from baseline to week 52. RESULTS: Baseline mean ± standard deviation of age, duration of diabetes and HbA1c were 56.1 ± 9.7 years, 7.8 ± 6.4 years and 8.5% ± 0.8% (69 ± 9.0 mmol/mol), respectively. Adjusted mean change from baseline in HbA1c was -1.35% (-14.8 mmol/mol) with DAPA + SAXA versus -0.98% (-10.7 mmol/mol) with GLIM (P <0.001). Changes from baseline in body weight and systolic blood pressure were -3.1 kg and -2.6 mmHg with DAPA + SAXA versus +1.0 kg (P <0.001) and +1.0 mmHg (P = 0.007) with GLIM. More patients achieved HbA1c <7.0% (53 mmol/mol) (44.3% vs. 34.3%; P = 0.044), and fewer patients required treatment intensification (1.3% vs. 8.8%; P = 0.002) with DAPA + SAXA than with GLIM. CONCLUSIONS: Compared with GLIM, concurrent addition of DAPA + SAXA significantly improved glycaemic control, body weight and other metabolic parameters in patients inadequately controlled on metformin. Trial: NCT02419612, ClinicalTrials.gov.

Prefronto-temporal white matter microstructural alterations 20 years after the diagnosis of type 1 diabetes mellitus.

OBJECTIVE: Microvascular pathophysiology that uniquely manifests as white matter (WM) abnormalities is often implicated in type 1 diabetes mellitus (T1DM)-related central nervous system (CNS) complications. This study sought to identify regional WM abnormalities in young adults diagnosed with T1DM and further examine their association with cognitive and emotional dysfunction. RESEARCH DESIGN AND METHODS: Diffusion tensor images (DTI) obtained from 34 young adults with T1DM for ≥15 years (mean duration, 20.9 years), and 16 age- and sex-matched healthy control subjects were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) values of the whole brain were analyzed, and their associations with memory function and depressive symptoms were assessed. RESULTS: Whole brain voxel-wise analyses showed that T1DM-related FA reductions were most prominent within the fronto-temporo-parietal regions of the brain. Reduced FA values in the bilateral superior longitudinal fasciculi, at which group differences were most prominent, correlated with lower working memory performance in young adults with T1DM (left, P < .001; right, P = .009). Subsyndromal depressive symptoms were also associated with lower FA values in the right inferior fronto-occipital fasciculus (P = .004). CONCLUSION: Widespread WM microstructural abnormalities in the fronto-temporo-parietal brain regions, which are associated with emotional and cognitive dysfunction, may be a contributing factor to the neural mechanisms underlying T1DM-related CNS complications, thus affecting the quality of life in young adults with T1DM.

REDUCED IMPACT OF DIABETES CLINIC REFERRAL ON HIGH-FREQUENCY EMERGENCY DEPARTMENT USERS.

OBJECTIVE: The patterns of emergency department (ED) visits in patients with diabetes are not well understood. The Emergency Department Diabetes Rapid-referral Program (EDRP) allows direct booking of ED patients presenting with urgent diabetes needs into a diabetes specialty clinic within 1 day of ED discharge. The objective of this secondary analysis was to examine characteristics of patients with diabetes who have frequent ED visits and determine reasons for revisits. METHODS: A single-center analysis was conducted comparing patients referred to the EDRP (n = 420) to historical unexposed controls (n = 791). The primary outcome was the proportion of patients in each frequency group of ED revisits (none, 1 to 3 [infrequent], 4 to 10 [frequent], or >10 [superfrequent]) in the year after the ED index visit. Secondary outcomes were hospitalization rates and International Classification of Diseases-Ninth Revision (ICD-9) diagnoses at ED revisits. RESULTS: Superfrequent users, responsible for >20% of total ED visits, made up small but not significantly different proportions of EDRP and control populations, 3.6% and 5.2%, respectively. Superfrequent groups had lower hospital admission rates at ED revisits compared to frequent groups. Mental health disorders (including substance abuse) were the primary, secondary, or tertiary ICD-9 codes in 30.6% (95% confidence interval [CI], 27.7% to 33.5%) and 6.6% (95% CI, 5.1% to 8.2%) in the superfrequent and infrequent groups, respectively. CONCLUSION: Direct access to diabetes specialty care from the ED is effective in reducing ED recidivism but not amongst a small subgroup of superfrequent ED users. This group was more likely to have mental health disorders recorded at ED revisits, suggesting that more comprehensive approaches are needed for this population. ABBREVIATIONS: EDRP = Emergency Department Diabetes Rapid-referral Program; ED = emergency department; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases-Ninth Revision.

Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Overweight and obesity may significantly worsen glycaemic and metabolic control in type 2 diabetes. However, little is known about the effects of overweight and obesity on the brains of people with type 2 diabetes. Here, we investigate whether the presence of overweight or obesity influences the brain and cognitive functions during early stage type 2 diabetes. METHODS: This study attempted to uncouple the effects of overweight/obesity from those of type 2 diabetes on brain structures and cognition. Overweight/obese participants with type 2 diabetes had more severe and progressive abnormalities in their brain structures and cognition during early stage type 2 diabetes compared with participants with normal weight. Relationships between each of these measures and disease duration were also examined. RESULTS: Global mean cortical thickness was lower in the overweight/obese type 2 diabetes group than in the normal-weight type 2 diabetes group (z = -2.96, p for group effect = 0.003). A negative correlation was observed between disease duration and global mean white matter integrity (z = 2.42, p for interaction = 0.02) in the overweight/obese type 2 diabetes group, but not in the normal-weight type 2 diabetes group. Overweight/obese individuals with type 2 diabetes showed a decrease in psychomotor speed performance related to disease duration (z = -2.12, p for interaction = 0.03), while normal-weight participants did not. CONCLUSIONS/INTERPRETATION: The current study attempted to uncouple the effects of overweight/obesity from those of type 2 diabetes on brain structures and cognition. Overweight/obese participants with type 2 diabetes had more severe and progressive abnormalities in brain structures and cognition during early stage type 2 diabetes compared with normal-weight participants.

Partial jejunal diversion using an incisionless magnetic anastomosis system: 1-year interim results in patients with obesity and diabetes.

BACKGROUND AND AIMS: Most patients with type 2 diabetes mellitus have obesity. Studies show that bariatric surgery is superior to medical treatment for remission of type 2 diabetes mellitus. Nevertheless, very few patients undergo surgery, and a less-invasive endoscopic alternative is desirable. METHODS: This was a single-arm first-in-human pilot study designed to evaluate the technical feasibility, safety, and clinical performance of the incisionless magnetic anastomosis system (IMAS) to create a partial jejunal diversion (PJD). Ten patients with obesity and type 2 diabetes mellitus, prediabetes, or no diabetes were enrolled. A PJD to the ileum was attempted in all patients under general anesthesia. The IMAS was delivered through the working channel of a colonoscope, with laparoscopic supervision. The patients were not required to participate in an intensive lifestyle/diet management program. Endoscopic visualization of the anastomosis was obtained at 2, 6, and 12 months. Patient weight, glycemic profile, and metabolic panels were acquired at 0.5, 1, 2, 3, 6, 9, and 12 months. RESULTS: A PJD was created in all patients with no device-related serious adverse events. The anastomosis remained widely patent in all patients at 1 year. Average total weight loss was 14.6% (40.2% excess weight loss at 12 months). A significant reduction in glycated hemoglobin level was observed in all diabetic (1.9%) and prediabetic (1.0%) patients, while reducing or eliminating the use of diabetes medications. CONCLUSIONS: Permanent anastomosis for PJD was created in all patients with the IMAS. This resulted in improvement in measures of hyperglycemia and progressive weight loss. (Clinical trial registration number: NCT02839512.).

Functional Connectivity of Insula, Basal Ganglia, and Prefrontal Executive Control Networks during Hypoglycemia in Type 1 Diabetes.

Human brain networks mediating interoceptive, behavioral, and cognitive aspects of glycemic control are not well studied. Using group independent component analysis with dual-regression approach of functional magnetic resonance imaging data, we examined the functional connectivity changes of large-scale resting state networks during sequential euglycemic-hypoglycemic clamp studies in patients with type 1 diabetes and nondiabetic controls and how these changes during hypoglycemia were related to symptoms of hypoglycemia awareness and to concurrent glycosylated hemoglobin (HbA1c) levels. During hypoglycemia, diabetic patients showed increased functional connectivity of the right anterior insula and the prefrontal cortex within the executive control network, which was associated with higher HbA1c. Controls showed decreased functional connectivity of the right anterior insula with the cerebellum/basal ganglia network and of temporal regions within the temporal pole network and increased functional connectivity in the default mode and sensorimotor networks. Functional connectivity reductions in the right basal ganglia were correlated with increases of self-reported hypoglycemic symptoms in controls but not in patients. Resting state networks that showed different group functional connectivity during hypoglycemia may be most sensitive to glycemic environment, and their connectivity patterns may have adapted to repeated glycemic excursions present in type 1 diabetes. Our results suggest that basal ganglia and insula mediation of interoceptive awareness during hypoglycemia is altered in type 1 diabetes. These changes could be neuroplastic adaptations to frequent hypoglycemic experiences. Functional connectivity changes in the insula and prefrontal cognitive networks could also reflect an adaptation to changes in brain metabolic pathways associated with chronic hyperglycemia. SIGNIFICANCE STATEMENT: The major factor limiting improved glucose control in type 1 diabetes is the significant increase in hypoglycemia associated with insulin treatment. Repeated exposure to hypoglycemia alters patients' ability to recognize the autonomic and neuroglycopenic symptoms associated with low plasma glucose levels. We examined brain resting state networks during the induction of hypoglycemia in diabetic and control subjects and found differences in networks involved in sensorimotor function, cognition, and interoceptive awareness that were related to chronic levels of glycemic control. These findings identify brain regions that are sensitive to variations in plasma glucose levels and may also provide a basis for understanding the mechanisms underlying the increased incidence of cognitive impairment and affective disorders seen in patients with diabetes.

OPEN ACCESS TO DIABETES CENTER FROM THE EMERGENCY DEPARTMENT REDUCES HOSPITALIZATIONS IN THE SUSEQUENT YEAR.

OBJECTIVE: Patients who present to the emergency department (ED) for diabetes without hyperglycemic crisis are at risk of unnecessary hospitalizations and poor outcomes. To address this, the ED Diabetes Rapid-referral Program (EDRP) was designed to provide ED staff with direct booking into the diabetes center. The objective of this study was to determine the effects of the EDRP on hospitalization rate, ED utilization rate, glycemic control, and expenditures. METHODS: We conducted a single-center analysis of the EDRP cohort (n = 420) and compared 1-year outcomes to historic controls (n = 791). We also compared EDRP patients who arrived (ARR) to those who did not show (NS). The primary outcome was hospitalization rate over 1 year. Secondary outcomes included ED recidivism rate, hemoglobin A1c (HbA1c), and healthcare expenditures. RESULTS: Compared with controls, the EDRP cohort was less likely to be hospitalized (27.1% vs. 41.5%, P<.001) or return to the ED (52.2% vs. 62.3%, P = .001) at the end of 1 year. Total hospitalizations were also lower in the EDRP (157 ± 19 vs. 267 ± 18 per 1,000 persons per year, P<.001). The EDRP cohort had a greater reduction in HbA1c (-2.66 vs. -2.01%, P<.001), which was more pronounced when ARR patients were compared with NS (-2.71% vs. -1.37%, P<.05). The mean per patient institutional healthcare expenditures were lower by $5,461 compared with controls. CONCLUSION: Eliminating barriers to scheduling diabetes-focused ambulatory care for ED patients was associated with significant reductions in hospitalization rate, ED recidivism rate, HbA1c, and healthcare expenditures in the subsequent year. ABBREVIATIONS: ARR = arrived ED = emergency department EDRP = emergency department diabetes rapid-referral Program HbA1c = hemoglobin A1c NS = no show.

Surrogate measures of insulin resistance: does one size fit all?

Insulin resistance and a relative deficiency in insulin secretion are the major pathophysiological features of impaired glucose tolerance and type 2 diabetes. Although the euglycaemic-hyperinsulinaemic clamp and the hyperglycaemic clamp are the 'gold standards', respectively, for measuring these metabolic defects, there has been an active search during the past few decades for simpler and less expensive surrogate measures of insulin resistance that can be applied more globally in epidemiological studies or large clinical trials. These surrogate markers primarily rely on plasma insulin and glucose levels measured either in the fasting state or after an oral glucose challenge. Although many of these surrogate measures correlate well with the clamp (with r values frequently as high as 0.60-0.70) within racially and ethnically homogeneous populations, it is not clear how well they can be used to compare insulin action across different groups. In this issue of Diabetologia, Ahuja et al (DOI: 10.1007/s00125-014-3414-6 ) have used these methods to compare insulin resistance in a white population in the USA with a Japanese population in Japan. The relative merits and drawbacks of applying these techniques in different populations are discussed.

Continuous Glucose Monitoring Profiles and Health Outcomes after Dapagliflozin Plus Saxagliptin vs Insulin Glargine.

CONTEXT: Glycemic variability and hypoglycemia during diabetes treatment may impact therapeutic effectiveness and safety, even when glycated hemoglobin (HbA1c) reduction is comparable between therapies. OBJECTIVE: We employed masked continuous glucose monitoring (CGM) during a randomized trial of dapagliflozin plus saxagliptin (DAPA+SAXA) vs insulin glargine (INS) to compare glucose variability and patient-reported outcomes (PROs). DESIGN: 24-week sub-study of a randomized, open-label, two-arm, parallel-group, phase 3b study. SETTING: Multicenter study (112 centers in 11 countries). PATIENTS: 283 adults with type 2 diabetes (T2D) inadequately controlled with metformin ± sulfonylurea. INTERVENTIONS: DAPA+SAXA vs INS. MAIN OUTCOME MEASURES: Changes in CGM profiles, HbA1c, and PROs. RESULTS: Changes from baseline in HbA1c with DAPA+SAXA were similar to those observed with INS, with mean difference [95% CI] between decreases of -0.12% [-0.37 to 0.12%], P = .33. CGM analytics were more favorable for DAPA+SAXA, including greater percent time in range (> 3.9 and ≤ 10 mmol/L; 34.3 ± 1.9 vs 28.5 ± 1.9%, P = .033), lower percent time with nocturnal hypoglycemia (area under the curve ≤ 3.9 mmol/L; 0.6 ± 0.5 vs 2.7 ± 0.5%, P = .007), and smaller mean amplitude of glycemic excursions (-0.7 ± 0.1 vs -0.3 ± 0.1 mmol/L, P = .017). Improvements in CGM were associated with greater satisfaction, better body weight image, less weight interference, and improved mental and emotional well-being. CONCLUSIONS: DAPA+SAXA and INS were equally effective in reducing HbA1c at 24 weeks, but people with T2D treated with DAPA+SAXA achieved greater time in range, greater reductions in glycemic excursions and variability, less time with hypoglycemia, and improved patient-reported health outcomes.

Predictors of readmission and mortality in adults with diabetes or stress hyperglycemia after initial hospitalization for COVID-19.

INTRODUCTION: We previously reported predictors of mortality in 1786 adults with diabetes or stress hyperglycemia (glucose>180 mg/dL twice in 24 hours) admitted with COVID-19 from March 2020 to February 2021 to five university hospitals. Here, we examine predictors of readmission. RESEARCH DESIGN AND METHODS: Data were collected locally through retrospective reviews of electronic medical records from 1786 adults with diabetes or stress hyperglycemia who had a hemoglobin A1c (HbA1c) test on initial admission with COVID-19 infection or within 3 months prior to initial admission. Data were entered into a Research Electronic Data Capture (REDCap) web-based repository, and de-identified. Descriptive data are shown as mean±SD, per cent (%) or median (IQR). Student's t-test was used for comparing continuous variables with normal distribution and Mann-Whitney U test was used for data not normally distributed. X2 test was used for categorical variable. RESULTS: Of 1502 patients who were alive after initial hospitalization, 19.4% were readmitted; 90.3% within 30 days (median (IQR) 4 (0-14) days). Older age, lower estimated glomerular filtration rate (eGFR), comorbidities, intensive care unit (ICU) admission, mechanical ventilation, diabetic ketoacidosis (DKA), and longer length of stay (LOS) during the initial hospitalization were associated with readmission. Higher HbA1c, glycemic gap, or body mass index (BMI) were not associated with readmission. Mortality during readmission was 8.0% (n=23). Those who died were older than those who survived (74.9±9.5 vs 65.2±14.4 years, p=0.002) and more likely had DKA during the first hospitalization (p<0.001). Shorter LOS during the initial admission was associated with ICU stay during readmission, suggesting that a subset of patients may have been initially discharged prematurely. CONCLUSIONS: Understanding predictors of readmission after initial hospitalization for COVID-19, including older age, lower eGFR, comorbidities, ICU admission, mechanical ventilation, statin use and DKA but not HbA1c, glycemic gap or BMI, can help guide treatment approaches and future research in adults with diabetes.

Glycemic Gap Predicts Mortality in a Large Multicenter Cohort Hospitalized With COVID-19.

CONTEXT: Diabetes or hyperglycemia at admission are established risk factors for adverse outcomes during hospitalization for COVID-19, but the impact of prior glycemic control is not clear. OBJECTIVE: We aimed to examine the associations between admission variables, including glycemic gap, and adverse clinical outcomes in patients hospitalized with COVID-19 infection. METHODS: We examined the relationship between clinical predictors, including acute and chronic glycemia, and clinical outcomes, including intensive care unit (ICU) admission, mechanical ventilation (MV), and mortality among 1786 individuals with diabetes or hyperglycemia (glucose > 10 mmol/L twice in 24 hours) who were admitted from March 2020 through February 2021 with COVID-19 infection at 5 university hospitals in the eastern United States. RESULTS: The cohort was 51.3% male, 53.3% White, 18.8% Black, 29.0% Hispanic, with age = 65.6 ± 14.4 years, BMI = 31.5 ± 7.9 kg/m2, glucose = 12.0 ± 7.5 mmol/L [216 ± 135 mg/dL], and HbA1c = 8.07% ± 2.25%. During hospitalization, 38.9% were admitted to the ICU, 22.9% received MV, and 10.6% died. Age (P < 0.001) and admission glucose (P = 0.014) but not HbA1c were associated with increased risk of mortality. Glycemic gap, defined as admission glucose minus estimated average glucose based on HbA1c, was a stronger predictor of mortality than either admission glucose or HbA1c alone (OR = 1.040 [95% CI: 1.019, 1.061] per mmol/L, P < 0.001). In an adjusted multivariable model, glycemic gap, age, BMI, and diabetic ketoacidosis on admission were associated with increased mortality, while higher estimated glomerular filtration rate (eGFR) and use of any diabetes medication were associated with lower mortality (P < 0.001). CONCLUSION: Relative hyperglycemia, as measured by the admission glycemic gap, is an important marker of mortality risk in COVID-19.

Gaining metabolic insight in older men undergoing androgen deprivation therapy for prostate cancer (the ADT & Metabolism Study): Protocol of a longitudinal, observational, cohort study.

Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.

Diabetes Remission in the Alliance of Randomized Trials of Medicine Versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D).

OBJECTIVE: The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS: A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N = 195) or medical/lifestyle therapy (N = 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c [HbA1c] ≤6.5% for 3 months without usual glucose-lowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS: Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m2, and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA1c (Δ = -1.9 ± 2.0 vs. -0.1 ± 2.0%; P < 0.001), fasting plasma glucose (Δ = -52 [-105, -5] vs. -12 [-48, 26] mg/dL; P < 0.001), and BMI (Δ = -8.0 ± 3.6 vs. -1.8 ± 2.9 kg/m2; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). CONCLUSIONS: Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used.

High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control.

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020.