Sri Prakash Mokshagundam

Adipose tissue and reproduction in women

Adipose tissue has been viewed as the primary source of stored energy, but with the discovery of novel adipose tissue gene products, i.e., adipokines, another equally important role has emerged. Adipose tissue is a key endocrine organ involved in multiple processes, including glucose homeostasis, steroid production, immunoregulation, hematopoesis, and reproduction. The distribution of adipose tissue may also have a significant impact on reproductive function.

Local growth factors are beneficial for the autonomic reinnervation of transplanted islets in rats

Introduction Transplanted islets, being avascular and denervated, receive blood vessels and nerves from the recipient. Reinnervation may account in part for the normalization of islet function in islet transplants. Whether reinnervation is possible to augment is not known. Aims and Methodology To explore whether reinnervation of transplanted islets is augmented by local addition of growth factors to the graft, syngeneic islets were transplanted to the pancreas of streptozotocin-diabetic Lewis rats with or without pellets locally releasing nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), alone or in combination. The pellets released growth factors for 14 days at a rate of 20 ng/day. After 7 weeks, pancreatic tissue was processed for immunofluorescence of insulin and the neural markers neuropeptide Y (NPY) and tyrosine hydroxylase (TH). Results Islets were larger and more numerous after treatment with NGF (p = 0.024) and with NGF in combination with VEGF (p = 0.044). Similarly, immunostaining for TH and the C-terminal flanking peptide of NPY (C-PON) was more pronounced after treatment with NGF in combination with VEGF than in controls (both p < 0.05). Conclusion Local growth factor treatment has a beneficial effect on autonomic reinnervation as well as islet integrity and survival of the graft after islet transplantation in rats.

S-Adenosylmethionine Decreases Lipopolysaccharide-Induced Phosphodiesterase 4B2 and Attenuates Tumor Necrosis Factor Expression via cAMP/Protein Kinase A Pathway

S-Adenosylmethionine (SAM) treatment has anti-inflammatory, cytoprotective effects against endotoxin-induced organ injury. An important component of the anti-inflammatory action of SAM involves down-regulation of the lipopolysaccharide (LPS)-induced transcriptional induction of tumor necrosis factor-α (TNF) expression by monocytes/macrophages. We examined the effect of SAM on expression and activity of LPS-induced up-regulation of phosphodiesterase 4 (PDE4), which regulates cellular cAMP levels and TNF expression. LPS treatment of RAW 264.7, a mouse macrophage cell line, led to the induction of Pde4b2 mRNA expression with no effect on Pde4a or Pde4d. SAM pretreatment led to a significant decrease in LPS-induced up-regulation of Pde4b2 expression in both RAW 264.7 cells and primary human CD14+ monocytes. Of note, the decreased Pde4b2 mRNA expression correlated with the SAM-dependent increase in the transcriptionally repressive histone H3 lysine 9 trimethylation on the Pde4b2 intronic promoter region. The SAM-mediated decrease in LPS-inducible Pde4b2 up-regulation resulted in an increase in cellular cAMP levels and activation of cAMP-dependent protein kinase A (PKA), which plays an inhibitory role in LPS-induced TNF production. In addition, SAM did not affect LPS-inducible inhibitor of nuclear factor-κB degradation or nuclear factor-κB (NF-κB)-p65 translocation into the nucleus but rather inhibited NF-κB transcriptional activity. These results demonstrate for the first time that inhibition of LPS-induced PDE4B2 up-regulation and increased cAMP-dependent PKA activation are significant mechanisms contributing to the anti-TNF effect of SAM. Moreover, these data also suggest that SAM may be used as an effective PDE4B inhibitor in the treatment of chronic inflammatory disorders in which TNF expression plays a significant pathogenic role.

Development and validation of The Personal Diabetes Questionnaire (PDQ): A measure of diabetes self-care behaviors, perceptions and barriers

AIM To develop and evaluate the validity and reliability of The Personal Diabetes Questionnaire (PDQ), a brief, yet comprehensive measure of diabetes self-care behaviors, perceptions and barriers. To examine individual items to provide descriptive and normative information and provide data on scale reliability and associations between PDQ scales and concurrently assessed HBA(1c) and BMI. METHOD Items were written to address nutritional management, medication utilization, blood glucose monitoring, and physical activity. The initial instrument was reviewed by multidisciplinary diabetes care providers and items subsequently revised until the measure provided complete coverage of the diabetes care domains using as few items as possible. The scoring scheme was generated rationally. Subjects were 790 adults (205 with type 1 and 585 with type 2 diabetes) who completed the PDQ while waiting for clinic appointments. RESULTS Item completion rates were high, with few items skipped by participants. Subscales demonstrated good internal consistency (Cronbach α=.650-.834) and demonstrated significant associations with BMI (p ≤.001) and HbA(1c) (p ≤.001). CONCLUSIONS The PDQ is a useful measure of diabetes self-care behaviors and related perceptions and barriers that is reliable and valid and feasible to administer in a clinic setting. This measure may be used to obtain data for assessing diabetes self-management and barriers and to guide patient care.

Interstitial insulin during euglycemic-hyperinsulinemic clamp in obese and lean individuals.

Transcapillary insulin transport has been considered a rate-limiting step of insulin action. However, direct measurement of interstitial insulin levels during physiologic levels of insulinemia have not been performed. We determined changes in interstitial insulin in eight healthy non-obese men and seven healthy obese men by microdialysis during a euglycemic-hyperinsulinemic clamp. Interstitial insulin was determined in the subcutaneous tissue of the abdomen and thigh. Steady-state insulin concentrations were reached approximately 10 minutes after the start of insulin infusion in the subcutaneous tissue of the abdomen and thigh and returned to basal levels approximately 10 minutes after the infusion was discontinued. There was no difference in the rapidity of change in interstitial insulin between obese and lean individuals at either site studied, irrespective of the pattern of fat distribution. The relative change in dialysate insulin concentration during the euglycemic clamp did not differ between obese and lean individuals at either site studied. It was also unaffected by the waist to hip ratio. The rapid change in interstitial insulin concentration could be of physiologic significance in determining the effects of changes in circulating insulin concentration. We conclude that transcapillary insulin transport in adipose tissue is unaffected by obesity and the pattern of fat distribution in healthy men. It is also concluded that when interstitial insulin is determined directly, transcapillary insulin transport is rapid and does not demonstrate a significant lag phase.

Diet self-management and readiness to change in underserved adults with type 2 diabetes.

AIM Dietary assessment in diabetes may be enhanced by considering patient-centered perspectives and barriers to change within IDF guidelines. Consideration of readiness to change (RTC) diet in underserved samples may guide future interventions in high risk populations. This study assesses the utility of a rapid assessment of RTC diet in a medically underserved sample. METHOD Participants were 253 Black (43.7%) and White (55.1%) American adults with type 2 diabetes [M age=57.93 (11.52); 60.5% female; 19% below the US poverty threshold]. Participants were recruited at medical clinics and completed validated self-report measures assessing diabetes knowledge, self-efficacy and dietary behaviors and barriers by RTC. RESULTS Stage-based comparisons identified significant differences in diabetes and dietary domains: participants in the Action stage endorsed fewer behavioral dietary barriers (p<.001), more frequent dietary problem-solving (p<.001), and greater diabetes self-efficacy (p<.001) than participants in the Contemplation and Preparation stages. Women were more likely to be in the Preparation stage and beyond (p<.05). CONCLUSIONS Findings highlight the clinical utility of a brief measure of RTC in understanding patient perspectives toward dietary behaviors in a medically underserved sample. The impact of gender on RTC diet warrants further exploration.

Beneficial effect of recombinant rC1rC2 collagenases on human islet function: Efficacy of low-dose enzymes on pancreas digestion and yield

A high number of human islets can be isolated by using modern purified tissue dissociation enzymes; however, this requires the use of >20 Wunsch units (WU)/g of pancreas for digestion. Attempts to reduce this dose have resulted in pancreas underdigestion and poor islet recovery but improved islet function. In this study, we achieved a high number of functional islets using a low dose of recombinant collagenase enzyme mixture (RCEM‐1200 WU rC2 and 10 million collagen‐degrading activity [CDA] U of rC1 containing about 209 mg of collagenase to digest a 100‐g pancreas). The collagenase dose used in these isolations is about 42% of the natural collagenase enzyme mixture (NCEM) dose commonly used to digest a 100‐g pancreas. Low‐dose RCEM was efficient in digesting entire pancreases to obtain higher yield (5535 ± 830 and 2582 ± 925 islet equivalent/g, P < .05) and less undigested tissue (16.7 ± 5% and 37.8 ± 3%, P < .05) compared with low‐dose NCEM (12WU/g). Additionally, low‐dose RCEM islets retained better morphology (confirmed with scanning electron microscopy) and higher in vitro basal insulin release (2391 ± 1342 and 1778 ± 978 μU/mL; P < .05) compared with standard‐dose NCEM. Nude mouse bioassay demonstrated better islet function for low‐dose RCEM (area under the curve [AUC] 24 968) compared with low‐dose (AUC–38 225) or standard‐dose NCEM (AUC–38 685), P < .05. This is the first report indicating that islet function can be improved by using low‐dose rC1rC2 (RCEM).

Intra-islet endothelial cell and β-cell crosstalk: Implication for islet cell transplantation

The intra-islet microvasculature is a critical interface between the blood and islet endocrine cells governing a number of cellular and pathophysiological processes associated with the pancreatic tissue. A growing body of evidence indicates a strong functional and physical interdependency of β-cells with endothelial cells (ECs), the building blocks of islet microvasculature. Intra-islet ECs, actively regulate vascular permeability and appear to play a role in fine-tuning blood glucose sensing and regulation. These cells also tend to behave as “guardians”, controlling the expression and movement of a number of important immune mediators, thereby strongly contributing to the physiology of islets. This review will focus on the molecular signalling and crosstalk between the intra-islet ECs and β-cells and how their relationship can be a potential target for intervention strategies in islet pathology and islet transplantation.

Self-Reported Physical Activity in Medically Underserved Adults with Type 2 Diabetes in Clinical and Community Settings

BACKGROUND This study assessed physical activity (PA) in community dwelling adults with Type 2 diabetes, using multiple instruments reflecting internationally normed PA and diabetes-specific self-care behaviors. METHODS Two hundred and fifty-three Black (44.8%) and White (55.2%) Americans [mean age = 57.93; 39.5% male] recruited at low-income clinic and community health settings. Participants completed validated PA self-report measures developed for international comparisons (International Physical Activity Questionnaire Short Form), characterization of diabetes self-care (Summary of Diabetes Self-Care Activities Measure; SDSCA) and exercise-related domains including provider recommendations and PA behaviors and barriers (Personal Diabetes Questionnaire; PDQ). RESULTS Self-reported PA and PA correlates differed by instrument. BMI was negatively correlated with PA level assessed by the PDQ in both genders, and assessed with SDSCA activity items in females. PA levels were low, comparable to previous research with community and diabetes samples. Pain was the most frequently reported barrier; females reported more frequent PA barriers overall. CONCLUSIONS When using self-report PA measures for PA evaluation of adults with diabetes in clinical settings, it is critical to consider population and setting in selecting appropriate tools. PA barriers may be an important consideration when interpreting PA levels and developing interventions. Recommendations for incorporating these measures in clinical and research settings are discussed.

Feasibility of a pilot intervention targeting self-care behaviors in adults with diabetes mellitus

Diabetes has reached epidemic proportions and is widely encountered by clinicians in medical settings. National Standards for diabetes education recommend utilization of an interdisciplinary team, setting individual lifestyle goals and managing barriers. However, typical diabetes education programs lack integration of strategies for translating recommendations into behavioral actions. The present intervention was developed to assess the feasibility and efficacy of a short-term cognitive-behavioral intervention aimed at optimizing self-care behaviors in adults with diabetes in a “real world” medical setting. Participants were 20 adults who had completed medical model outpatient diabetes education. The intervention consisted of 6 weekly sessions that addressed the role of behavior in diabetes including self-care barriers, cognitions and self-regulation. Pre-post intervention data indicated greater specificity in goal-setting. Participants who kept activity records had the greatest lifestyle activity behavior change. Findings suggest that a brief intervention addressing realistic goal-setting is feasible and can promote meaningful health behavior changes. Clinical psychology can provide a bridge between current diabetes care recommendations and available medical resources by providing training in and delivery of empirically supported behavior change strategies and evaluation of diabetes care treatment approaches.