Umesh Masharani

Diabetes Distress but Not Clinical Depression or Depressive Symptoms Is Associated With Glycemic Control in Both Cross-Sectional and Longitudinal Analyses

OBJECTIVE To determine the concurrent, prospective, and time-concordant relationships among major depressive disorder (MDD), depressive symptoms, and diabetes distress with glycemic control. RESEARCH DESIGN AND METHODS In a noninterventional study, we assessed 506 type 2 diabetic patients for MDD (Composite International Diagnostic Interview), for depressive symptoms (Center for Epidemiological Studies-Depression), and for diabetes distress (Diabetes Distress Scale), along with self-management, stress, demographics, and diabetes status, at baseline and 9 and 18 months later. Using multilevel modeling (MLM), we explored the cross-sectional relationships of the three affective variables with A1C, the prospective relationships of baseline variables with change in A1C over time, and the time-concordant relationships with A1C. RESULTS All three affective variables were moderately intercorrelated, although the relationship between depressive symptoms and diabetes distress was greater than the relationship of either with MDD. In the cross-sectional MLM, only diabetes distress but not MDD or depressive symptoms was significantly associated with A1C. None of the three affective variables were linked with A1C in prospective analyses. Only diabetes distress displayed significant time-concordant relationships with A1C. CONCLUSIONS We found no concurrent or longitudinal association between MDD or depressive symptoms with A1C, whereas both concurrent and time-concordant relationships were found between diabetes distress and A1C. What has been called “depression” among type 2 diabetic patients may really be two conditions, MDD and diabetes distress, with only the latter displaying significant associations with A1C. Ongoing evaluation of both diabetes distress and MDD may be helpful in clinical settings.

Clinical Depression Versus Distress Among Patients With Type 2 Diabetes: Not Just a Question of Semantics

OBJECTIVE—We sought to determine differences between structured interviews, symptom questionnaires, and distress measures for assessment of depression in patients with diabetes. RESEARCH DESIGN AND METHODS—We assessed 506 diabetic patients for major depressive disorder (MDD) by a structured interview (Composite International Diagnostic Interview [CIDI]), a questionnaire for depressive symptoms (Center for Epidemiological Studies Depression Scale [CESD]), and on the Diabetes Distress Scale. Demographic characteristics, two biological variables (A1C and non-HDL cholesterol), and four behavioral management measures (kilocalories, calories of saturated fat, number of fruit and vegetable servings, and minutes of physical activity) were assessed. Comparisons were made between those with and without depression on the CIDI and the CESD. RESULTS—Findings showed that 22% of patients reached CESD ≥16, and 9.9% met a CIDI diagnosis of MDD. Of those above CESD cut points, 70% were not clinically depressed, and 34% of those who were clinically depressed did not reach CESD scores ≥16. Those scoring ≥16, compared with those <16 on the CESD, had higher A1C, kilocalories, and calories of saturated fat and lower physical activity. No differences were found using the CIDI. Diabetes distress was minimally related to MDD but substantively linked to CESD scores and to outcomes. CONCLUSIONS—Most patients with diabetes and high levels of depressive symptoms are not clinically depressed. The CESD may be more reflective of general emotional and diabetes-specific distress than clinical depression. Most treatment of distress, however, is based on the depression literature, which suggests the need to consider different interventions for distressed but not clinically depressed diabetic patients.

A longitudinal study of affective and anxiety disorders, depressive affect and diabetes distress in adults with Type 2 diabetes

Aims  To report the prevalence and correlates of affective and anxiety disorders, depressive affect and diabetes distress over time.

High-Resolution Peripheral Quantitative Computed Tomographic Imaging of Cortical and Trabecular Bone Microarchitecture in Patients with Type 2 Diabetes Mellitus

CONTEXT Cross-sectional epidemiological studies have found that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of certain fragility fractures despite normal or elevated bone mineral density (BMD). OBJECTIVE In this study, high-resolution peripheral quantitative computed tomography was applied to characterize cortical and trabecular microarchitecture and biomechanics in the peripheral skeleton of female patients with T2DM. DESIGN AND SETTING A cross-sectional study was conducted in patients with T2DM recruited from a diabetic outpatient clinic. PARTICIPANTS Elderly female patients (age, 62.9 ± 7.7 yr) with a history of T2DM (n = 19) and age- and height-matched controls (n = 19) were recruited. OUTCOME MEASURES Subjects were imaged using high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Quantitative measures of volumetric (BMD), cross-sectional geometry, trabecular and cortical microarchitecture were calculated. Additionally, compressive mechanical properties were determined by micro-finite element analysis. RESULTS Compared to the controls, the T2DM cohort had 10% higher trabecular volumetric BMD (P < 0.05) adjacent to the cortex and higher trabecular thickness in the tibia (13.8%; P < 0.05). Cortical porosity differences alone were consistent with impaired bone strength and were significant in the radius (>+50%; P < 0.05), whereas pore volume approached significance in the tibia (+118%; P = 0.1). CONCLUSION The results of this pilot investigation provide a potential explanation for the inability of standard BMD measures to explain the elevated fracture incidence in patients with T2DM. The findings suggest that T2DM may be associated with impaired resistance to bending loads due to inefficient redistribution of bone mass, characterized by loss of intracortical bone offset by an elevation in trabecular bone density.

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?†

To compare vertebral bone marrow fat content quantified with proton MR spectroscopy (1H‐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).

REDEEM: A Pragmatic Trial to Reduce Diabetes Distress

OBJECTIVE To compare three interventions to reduce diabetes distress (DD) and improve self-management among non–clinically depressed adults with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS In REDEEM, 392 adults with T2DM and DD were randomized to computer-assisted self-management (CASM), CASM plus DD-specific problem solving (CAPS), or a computer-administered minimal supportive intervention. Primary outcomes were Diabetes Distress Scale (DDS) total, the Emotional Burden (EB) and Regimen Distress (RD) DDS subscales, and diet, exercise, and medication adherence. RESULTS Significant and clinically meaningful reductions in DD (DDS, EB, and RD) and self-management behaviors occurred in all three conditions (P < 0.001), with no significant between-group differences. There was, however, a significant group × baseline distress interaction (P < 0.02), in which patients with high baseline RD in the CAPS condition displayed significantly larger RD reductions than those in the other two conditions. RD generated the most distress and displayed the greatest distress reduction as a result of intervention. The pace of DD reduction varied by patient age: older patients demonstrated significant reductions in DD early in the intervention, whereas younger adults displayed similar reductions later. Reductions in DD were accompanied by significant improvements in healthy eating, physical activity, and medication adherence, although not by change in HbA1c. CONCLUSIONS DD is malleable and highly responsive to intervention. Interventions that enhance self-management also reduce DD significantly, but DD-specific interventions may be necessary for patients with high initial levels of DD. Future research should identify the minimal, most cost-effective interventions to reduce DD and improve self-management.

Troglitazone-induced fulminant hepatic failure

Troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey), the first marketed member of a new class of oral agents for type II diabetes mellitus, the thiazolidinediones, has a number of attractive attributes. It reduces insulin resistance and increases insulin-stimulated glucose disposal, resulting in improved glycemic control and decreased insulin requirements in treated patients (1, 2). In addition, it is dosed once a day, is readily absorbed from the gastrointestinal tract, does not induce hypoglycemia, and does not appear to interact with other medications. Because of these attributes, troglitazone has enjoyed widespread use since its introduction in March 1997. In premarketing clinical trials of troglitazone, mild hepatotoxicity identified as reversible elevations of alanine aminotransferase (ALT) greater than three times normal were seen in less than 2% of treated patients (3). However, since the drug was released, several cases of more severe, even fatal, episodes of hepatitis have been reported (4–7). Here we report three cases of apparent troglitazone-induced fulminant liver failure prospectively identified through the Acute Liver Failure Study Group (ALFSG), a consortium of 14 academic medical centers with the purpose of collecting data regarding the etiology, treatment, and outcome of patients with acute liver failure. The cases highlight the potential hepatotoxicity of troglitazone and reinforce the need for close monitoring of all patients taking the drug.The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.

Islet Transplantation in Type 1 Diabetics Using an Immunosuppressive Protocol Based on the Anti-LFA-1 Antibody Efalizumab

The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen‐1 antibody efalizumab which permits long‐term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single‐islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long‐term follow‐up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid‐free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long‐term islet allograft survival.

Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade.

Background. The applicability of islet transplantation as treatment for type 1 diabetes is limited by long-term graft dysfunction, immunosuppressive drug toxicity, need for multiple donors, and increased risk of allosensitization. We describe two immunosuppressive regimens based on the costimulation blocker belatacept (BELA) or the antileukocyte functional antigen-1 antibody efalizumab (EFA), which permit long-term islet allograft survival and address some of these concerns. Methods. Ten patients with type 1 diabetes with hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction and maintenance with sirolimus or mycophenolate and BELA (n=5) or EFA (n=5). Results. All five BELA-treated patients achieved independence after single transplants; one resumed partial insulin use 305 days after transplant but is now independent after a second transplant. All five patients treated with EFA achieved independence after one (3/5) or two (2/5) islet transplants and remained independent while on EFA (392–804 days). After EFA was discontinued because of withdrawal of the drug from the market, two patients resumed intermittent insulin use; the others remain independent. No patient in either group developed significant side effects related to the study drugs, and none have been sensitized to alloantigens. All have stable renal function. Conclusions. These two novel immunosuppressive regimens are effective, well tolerated, and the first calcineurin inhibitor/steroid-sparing islet protocols resulting in long-term insulin independence. Although EFA is no longer available for clinical use, these early results demonstrate that a regimen using BELA may be an effective alternative to improve graft function and longevity while minimizing renal and &bgr;-cell toxicity.

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 Alzheimers 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 significandy 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.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimers disease. FASEB J. 29, 589‐596 (2015). www.fasebj.org