Altered Glucose Kinetics Occurs With Aging, A New Outlook on Metabolic Flexibility.

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers, along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios (RER=CO2/O2) during a 2-hour 75-gram oral glucose tolerance test (OGTT). After an 12-hour overnight fast, 28 participants, 15 young (21-35 yr.; 7 men and 8 women) and 13 older (60-80 yr.; 7 men and 6 women) received venous primed-continuous infusions of [6,6-2H]glucose, and [3-13C]lactate with a H13CO3- bolus. Following a 90-minute metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 minutes post-glucose consumption, peaked at 60 minutes, and remained elevated. As assessed by rates of appearance (Ra), disposal (Rd) and metabolic clearance (MCR) glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population following the oral glucose challenge. Lastly, there were no differences in 12-hr fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population following a glucose challenge. Further, those physiological deficits are not detected from changes in RER during an OGTT.

Effects of Alterations in Acid-Base Effects on Insulin Signaling.

Insulin tightly regulates glucose levels within a narrow range through its action on muscle, adipose tissue and the liver. The activation of insulin receptors activates multiple intracellular pathways with different functions. Another tightly regulated complex system in the body is acid-base balance. Metabolic acidosis, defined as a blood pH < 7.35 and serum bicarbonate < 22 mmol/L, has clear pathophysiologic consequences including an effect on insulin action. With the ongoing intake of typical acid-producing Western diets and the age-related decline in renal function, there is an increase in acid levels within the range considered to be normal. This modest increase in acidosis is referred to as "acid stress" and it may have some pathophysiological consequences. In this article, we discuss the effects of acid stress on insulin actions in different tissues.

A Case of Hypercalcemia from PTHrP-Producing Fibromyxoid Sarcoma Responsive to Glucocorticoid Therapy.

The treatment of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia of malignancy includes treating the malignancy, intravenous fluids, and anti-resorptive therapies such as zoledronic acid or denosumab. PTHrP-mediated hypercalcemia has been reported in benign conditions such as systemic lupus erythematous (SLE) and sarcoidosis and appears to be responsive to glucocorticoids. We report a case of PTHrP-induced hypercalcemia due to a malignancy-low grade fibromyxoid sarcoma-that responded to glucocorticoid treatment. This is the first report of glucocorticoids controlling PTHrP-mediated hypercalcemia of malignancy. Immunohistochemistry of the surgical pathology localized PTHrP staining to the vascular endothelial cells within the tumor. Further studies are needed to elucidate the mechanism of glucocorticoid action in the treatment of PTHrP-mediated hypercalcemia of malignancy.

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

The ubiquity of diabetes distress among adults with type 1 diabetes in an urban, academic practice: A template for intervention.

AIMS: The aim of this study was to assess the patterns of diabetes distress within an urban, technology-oriented academic clinical practice to inform staff training and intervention. METHODS: Adults with type 1 diabetes completed the Type 1 Diabetes Distress Scale at their regular clinic visit. Descriptive statistics were generated to document the prevalence of diabetes distress overall, and from seven primary sources of distress: powerlessness, disease management, hypoglycaemia, negative social perceptions, eating, physician and family/friends. Additional analyses explored relations between diabetes distress, demographic characteristics and disease status. RESULTS: The prevalence of elevated diabetes distress was 30% overall, with 88% of the sample reporting elevated distress from at least one primary source. Women reported more elevated distress overall, and from the primary sources. There was an inverse relationship between diabetes duration with total diabetes distress (r = -0.19) and with the powerlessness subscale (r = -0.28). Also, those without micro- and/or macrovascular complications more frequently reported elevated distress from powerlessness (85%) compared to those having complications (61%). Use of technology (continuous glucose monitoring, insulin pumps) was not significantly related to diabetes distress. Diabetes distress was positively correlated with HbA1c. About 22% of individuals with HbA1c <53 mmol/mol (<7%) had elevated total distress. About a third of the sample (34%-39%) reported elevated distress from powerlessness, hypoglycaemia, negative social perceptions, eating, or family/friends. CONCLUSIONS: It is critical to understand clinic-specific patterns of diabetes distress in order to customise staff training and intervention programmes, and thereby reduce distress among unique populations of adults with type 1 diabetes in different settings.

Hyperlactatemia in diabetic ketoacidosis.

AIMS: The study examined the prevalence and degree of lactate elevation in diabetic ketoacidosis, and explored which biochemical abnormalities predicted L-lactate levels. METHODS: We reviewed episodes of diabetic ketoacidosis from 79 diabetes patients (one episode per patient). Separate univariate linear regression models were specified to predict lactate level from each of nine biochemical variables. Significant predictors from the univariate models were included in a final multivariate linear regression model to predict lactate levels. RESULTS: Mean (SD) lactate level was 3.05 (1.66) mmol/L; about 65% of patients had lactate levels >2 mmol/L. In the final multivariate linear regression model (R2  = 0.45), higher lactate levels were associated with greater hydrogen ion concentration (standardised ß = .60, t = 4.16, p < 0.0001), higher blood glucose (standardised ß = .28, t = 2.67, p = 0.009) and lower glomerular filtration rate estimated from creatinine (standardised ß = -.23, t = 2.29, p = 0.025). Bicarbonate, beta-hydroxybutyrate, body mass index, mean arterial pressure and calculated osmolality were not significant predictors of lactate level. There were three distinct patterns of lactate levels with treatment of diabetic ketoacidosis: group 1 = gradual decline, group 2 = initial increase and then decline and group 3 = initial decline followed by a transient peak and subsequent decline. CONCLUSIONS: Elevated lactate level is the norm in patients with diabetic ketoacidosis. Higher blood glucose levels and higher hydrogen ion concentrations are related to greater lactate. With treatment, there are different patterns of decline in lactate levels.

Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair-bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP.

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease.

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.

A Case of Hypercalcemia and Overexpression of CYP27B1 in Skeletal Muscle Lesions in a Patient with HIV Infection After Cosmetic Injections with Polymethylmethacrylate (PMMA) for Wasting.

Foreign body-induced granuloma is an uncommon yet clinically significant cause of hypercalcemia. The molecular mechanisms are uncertain, although extrarenal calcitriol production has been proposed. We describe severe hypercalcemia associated with increased levels of plasma calcitriol in a patient with HIV and local granulomatous reaction 5 years after injection of polymethylmethacrylate (PMMA) as dermal filler for cosmetic body sculpting. Extensive evaluation revealed no identifiable cause of increased calcitriol levels. Nuclear imaging was remarkable for diffuse uptake in the subcutaneous tissues of the buttocks. Subsequent muscle biopsy and immunohistochemical staining showed strong local expression of CYP27B1 within histiocytes surrounding globules of PMMA. This case highlights an unfortunate complication of dermal fillers and shows that inflammatory cells can express high levels of CYP27B1 even without frank granulomas. The growing trend of body contour enhancement using injectable fillers should raise suspicion for this cause of hypercalcemia in clinical practice. Patients with HIV who receive this treatment for lipodystrophy or other cosmetic purposes may have increased susceptibility to hypercalcemia in the setting of underlying chronic inflammation. This may be a concern when changing anti-retroviral therapy, since alterations in levels of HIV viremia may initiate or contribute to worsening hypercalcemia.

Enteric and systemic postprandial lactate shuttle phases and dietary carbohydrate carbon flow in humans.

Dietary glucose in excess is stored in the liver in the form of glycogen. As opposed to direct conversion of glucose into glycogen, the hypothesis of the postprandial lactate shuttle (PLS) proposes that dietary glucose uptake is metabolized to lactate in the gut, thereby being transferred to the liver for glycogen storage. In the present study, we provide evidence of a PLS in young healthy men and women. Overnight fasted participants underwent an oral glucose tolerance test, and arterialized lactate concentration and rate of appearance were determined. The concentration of lactate in the blood rose before the concentration of glucose, thus providing evidence of an enteric PLS. Secondary increments in the concentration of lactate in the blood and its rate of appearance coincided with those of glucose, which indicates the presence of a larger, secondary, systemic PLS phase driven by hepatic glucose release. The present study challenges the notion that lactate production is the result of hypoxia in skeletal muscles, because our work indicates that glycolysis proceeds to lactate in fully aerobic tissues and dietary carbohydrate is processed via lactate shuttling. Our study proposes that, in humans, lactate is a major vehicle for carbohydrate carbon distribution and metabolism.

EMBARK: A Randomized, Controlled Trial Comparing Three Approaches to Reducing Diabetes Distress and Improving HbA1c in Adults With Type 1 Diabetes.

OBJECTIVE: To compare the effectiveness of three interventions to reduce diabetes distress (DD) and improve HbA1c among adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Individuals with T1D (n = 276) with elevated DD (a score >2 on the total Type 1 Diabetes Distress Scale) and HbA1c (>7.5%) were recruited from multiple settings and randomly assigned to one of three virtual group-based programs: 1) Streamline, an educator-led education and diabetes self-management program; 2) TunedIn, a psychologist-led program focused exclusively on emotional-focused DD reduction; or 3) FixIt, an integration of Streamline and TunedIn. Assessments of the primary outcomes of DD and HbA1c occurred at baseline and at 3, 6, and 12 months. RESULTS: All three programs demonstrated substantive and sustained reductions in DD (Cohen's d = 0.58-1.14) and HbA1c (range, -0.4 to -0.72) at 12-month follow-up. TunedIn and FixIt participants reported significantly greater DD reductions compared with Streamline participants (P = 0.007). Streamline and TunedIn participants achieved significantly greater HbA1c reductions than did FixIt participants (P = 0.006). CONCLUSIONS: DD can be successfully reduced among individuals with T1D with elevated HbA1c using both the educational/behavioral and emotion-focused approaches included in the study. Although both approaches are associated with significant and clinically meaningful reductions in DD and HbA1c, TunedIn, the emotion-focused program, had the most consistent benefits across both DD and HbA1c. The study findings suggest the overall value of group-based, fully virtual, and time-limited emotion-focused strategies, like those used in TunedIn, for adults with T1D.

Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis.

BACKGROUND: Prior research suggests clinical effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are mediated by changes in glycated hemoglobin, body weight, systolic blood pressure, hematocrit, and urine albumin-creatinine ratio. We aimed to confirm these findings using a meta-analytic approach. METHODS AND RESULTS: We updated a systematic review of 9 GLP-1RA and 13 SGLT2i trials and summarized longitudinal mediator data. We obtained hazard ratios (HRs) for cardiovascular, renal, and mortality outcomes. We performed linear mixed-effects modeling of LogHRs versus changes in potential mediators and investigated differences in meta-regression associations among drug classes using interaction terms. HRs generally became more protective with greater glycated hemoglobin reduction among GLP-1RA trials, with average HR improvements of 20% to 30%, reaching statistical significance for major adverse cardiovascular events (ΔHR, 23%; P=0.02). Among SGLT2i trials, associations with HRs were not significant and differed from GLP1-RA trials for major adverse cardiovascular events (Pinteraction=0.04). HRs for major adverse cardiovascular events, myocardial infarction, and stroke became less efficacious (ΔHR, -15% to -34%), with more weight loss for SGLT2i but not for GLP-1RA trials (ΔHR, 4%-7%; Pinteraction<0.05). Among 5 SGLT2i trials with available data, HRs for stroke became less efficacious with larger increases in hematocrit (ΔHR, 123%; P=0.09). No changes in HRs by systolic blood pressure (ΔHR, -11% to 9%) and urine albumin-creatinine ratio (ΔHR, -1% to 4%) were found for any outcome. CONCLUSIONS: We confirmed increased efficacy findings for major adverse cardiovascular events with reduction in glycated hemoglobin for GLP1-RAs. Further research is needed on the potential loss of cardiovascular benefits with increased weight loss and hematocrit for SGLT2i.

Cardiovascular and Renal Benefits of Novel Diabetes Drugs by Baseline Cardiovascular Risk: A Systematic Review, Meta-analysis, and Meta-regression.

BACKGROUND: Eligibility for glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but whether treatment benefits differ by risk levels is not clear. PURPOSE: To investigate whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RA and SGLT2i with use of meta-analysis and meta-regression. DATA SOURCES: We performed a systematic review using PubMed through 7 November 2022. STUDY SELECTION: We included reports of GLP-1RA and SGLT2i confirmatory randomized trials in adult patients with safety or efficacy end point data. DATA EXTRACTION: Hazard ratio (HR) and event rate data were extracted for mortality, cardiovascular, and renal outcomes. DATA SYNTHESIS: We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA 0.87 and SGLT2i 0.86), major adverse cardiovascular events (0.87 and 0.88), heart failure (0.89 and 0.70), and renal (0.84 and 0.65) outcomes. For stroke, efficacy was significant for GLP-1RA (0.84) but not for SGLT2i (0.92). Associations between control arm cardiovascular mortality rates and HRs were nonsignificant. Five-year absolute risk reductions (0.80-4.25%) increased to 11.6% for heart failure in SGLT2i trials in patients with high risk (Pslope < 0.001). For GLP1-RAs, associations were nonsignificant. LIMITATIONS: Analyses were limited by lack of patient-level data, consistency in end point definitions, and variation in cardiovascular mortality rates for GLP-1RA trials. CONCLUSIONS: Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making.

Use of Continuous Glucose Monitors in the Hospital: The Diabetes Technology Society Hospital Meeting Report 2023.

The annual Virtual Hospital Diabetes Meeting was hosted by the Diabetes Technology Society on April 14 and 15, 2023, with the goal of reviewing the progress made in the hospital use of continuous glucose monitors (CGMs). Meeting topics included (1) Nursing Issues, Protocols, Order Sets, and Staff Education for Using CGMs, (2) Implementing CGM Programs for Use in the Wards, (3) Quality Metrics and Financial Implications of CGMs in the Hospital, (4) CGMs in the Critical Care Setting, (5) Special Situations: Labor/Delivery and Hemodialysis, (6) Research Session on CGMs in the Hospital, (7) Starting a CGM on Hospitalized Patients, (8) Automated Insulin Delivery Systems in the Hospital, (9) CGMs in Children, (10) Data Integration of CGMs for Inpatient Use and Telemetry, (11) Accuracy of CGMs/Comparison with Point-of-care Blood Glucose Testing, and (12) Discharge Planning with CGMs. Outcome data as well as shared collective real-life experiences were reviewed, and expert recommendations for CGM implementation were formulated.

Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis.

Context: Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors. Objective: We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis). Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis. Results: Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma, and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure vs PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 vs 185 days, P < .01) and abnormal pituitary appearance on MRI (odds ratio 7.00, P = .03). We observed effect modification by sex in the association between CPI type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow-up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was over-represented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, P = 0.01) and CPI population. Conclusion: The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous, with differences in timing of onset, changes in thyroid function tests, MRI changes, and possibly sex related to CPI type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.

Diabetes Technology Meeting 2022.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 3 to November 5, 2022. Meeting topics included (1) the measurement of glucose, insulin, and ketones; (2) virtual diabetes care; (3) metrics for managing diabetes and predicting outcomes; (4) integration of continuous glucose monitor data into the electronic health record; (5) regulation of diabetes technology; (6) digital health to nudge behavior; (7) estimating carbohydrates; (8) fully automated insulin delivery systems; (9) hypoglycemia; (10) novel insulins; (11) insulin delivery; (12) on-body sensors; (13) continuous glucose monitoring; (14) diabetic foot ulcers; (15) the environmental impact of diabetes technology; and (16) spinal cord stimulation for painful diabetic neuropathy. A live demonstration of a device that can allow for the recycling of used insulin pens was also presented.

Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus?

PURPOSE: To compare vertebral bone marrow fat content quantified with proton MR spectroscopy ((1)H-MRS) with the volume of abdominal adipose tissue, lumbar spine volumetric bone mineral density (vBMD), and blood biomarkers in postmenopausal women with and without type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Thirteen postmenopausal women with T2DM and 13 age- and body mass index-matched healthy controls were included in this study. All subjects underwent (1)H-MRS of L1-L3 to quantify vertebral bone marrow fat content (FC) and unsaturated lipid fraction (ULF). Quantitative computed tomography (QCT) was performed to assess vBMD of L1-L3. The volumes of abdominal subcutaneous/visceral/total adipose tissue were determined from the QCT images and adjusted for abdominal body volume (SAT(adj)/VAT(adj)/TAT(adj)). Fasting blood tests included plasma glucose and HbA1c. RESULTS: Mean FC showed an inverse correlation with vBMD (r = -0.452; P < 0.05) in the whole study population. While mean FC was similar in the diabetic women and healthy controls (69.3 ± 7.5% versus 67.5 ± 6.1%; P > 0.05), mean ULF was significantly lower in the diabetic group (6.7 ± 1.0% versus 7.9 ± 1.6%; P < 0.05). SAT(adj) and TAT(adj) correlated significantly with mean FC in the whole study population (r = 0.538 and r = 0.466; P < 0.05). In contrast to the control group, significant correlations of mean FC with VAT(adj) and HbA1c were observed in the diabetic group (r = 0.642 and r = 0.825; P < 0.05). CONCLUSION: This study demonstrated that vertebral bone marrow fat content correlates significantly with SAT(adj), TAT(adj), and lumbar spine vBMD in postmenopausal women with and without T2DM, but with VAT(adj) and HbA1c only in women with T2DM.

Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity.

BACKGROUND: The use of chromium supplements is widespread for the prevention and treatment of diabetes mellitus but there are conflicting reports on efficacy, possibly reflecting discrepant effects across different populations. In the present studies, we test the hypothesis that chromium supplementation raises serum chromium levels and correspondingly improves insulin sensitivity. METHODS: A double blind placebo-controlled randomized trial was conducted on 31 non-obese, normoglycemic subjects. After baseline studies, the subjects were randomized to placebo or chromium picolinate 500 µg twice a day. The primary endpoint was change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Pre-specified secondary endpoints included fasting lipids, blood pressure, weight, body composition measured by DXA scan. RESULTS: After 16 weeks of chromium picolinate therapy there was no significant change in insulin sensitivity between groups (p=0.83). There was, however, a strong association between serum chromium and change in insulin resistance (ß = -0.83, p=0.01), where subjects with the highest serum chromium had a worsening of insulin sensitivity. This effect could not be explained by changes in physiological parameters such as body weight, truncal fat and serum lipids with chromium therapy. CONCLUSIONS: Chromium therapy did not improve insulin sensitivity in non-obese normoglycemic individuals. Further, subjects who have high serum chromium levels paradoxically had a decline in insulin sensitivity. Caution therefore should be exercised in recommending the use of this supplement. TRIAL REGISTRATION: The study was registered on the NIH registry (clinicaltrials.gov) and the identifier is NCT00846248.

Disconnected Pancreatic Duct Syndrome: Pancreatitis of the Disconnected Pancreas and Its Role in the Development of Diabetes Mellitus.

INTRODUCTION: Disconnected pancreatic duct syndrome (DPDS) is a recognized complication of necrotizing pancreatitis (NP). Manifestations include recurrent peripancreatic fluid collections (R-PFC) and pancreatocutaneous fistulae (PC-Fistulae). Pancreatitis of the disconnected pancreatic segment (DPDS-P) and its relationship to new-onset diabetes after pancreatitis (NODAP) are not well characterized. METHODS: We performed a retrospective cohort study of consecutive patients with NP admitted to University of California, San Francisco from January 2011 to June 2019. A diagnosis of a disconnected pancreatic duct (PD) was confirmed using computed tomography and magnetic resonance cholangiopancreatography/endoscopic retrograde cholangiopancreatography. DPDS was defined as a disconnected PD presenting with R-PFC, PC-Fistulae, or DPDS-P. The primary outcome was NODAP, defined as diabetes mellitus (DM) occurring >3 months after NP. Cox proportional hazards regression was used to evaluate the relationship between DPDS and NODAP. RESULTS: Of 171 patients with NP in this study, the mean clinical follow-up was 46 ± 18 months and the imaging follow-up was 38 ± 20 months. Twenty-seven patients (16%) developed DPDS-P at a median of 28 months. New-onset DM occurred in 54 of the 148 patients (36%), with 22% developing DM within 3 months of NP and 14% developing NODAP at a median of 31 months after AP. DPDS-P was associated with NODAP when compared with non-DPDS patients (adjusted hazard ratio 5.63 95% confidence interval: 1.69-18.74, P = 0.005) while R-PFCs and PC-Fistulae were not. DISCUSSION: DPDS and NODAP occurred in 28% and 14% of the patients, respectively. Pancreatitis of the disconnected pancreas occurred in 16% of the patients and was associated with higher rates of NODAP when compared with patients with other manifestations of DPDS and patients without DPDS.