Robert J. Rushakoff

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

It is known that the ingestion of glucose alone causes a greater increase in plasma glucose levels than ingestion of the same amount of glucose given with other nutrients. Since physiological plasma concentrations of cholecystokinin (CCK) prolong gastric emptying, it is proposed that after a meal, CCK may modify plasma glucose levels by delaying glucose delivery to the duodenum. To evaluate the effect of CCK on oral glucose tolerance, plasma CCK, insulin, and glucose levels and gastric emptying rates were measured in eight normal males before and after the ingestion of 60 g glucose with the simultaneous infusion of either saline or one of two doses of CCK-8 (12 or 24 pmol/kg per h). Gastric emptying rates were measured by gamma camera scintigraphy of technetium 99m sulfur colloid and plasma CCK levels were measured by a sensitive and specific bioassay. Basal CCK levels averaged 1.0 +/- 0.1 pM (mean +/- SEM, n = 8) and increased to 7.1 +/- 1.1 pM after a mixed liquid meal. After glucose ingestion, but without CCK infusion, CCK levels did not change from basal, and the gastric emptying t1/2 was 68 +/- 3 min. Plasma glucose levels increased from basal levels of 91 +/- 3.9 mg/dl to peak levels of 162 +/- 11 mg/dl and insulin levels increased from 10.7 +/- 1.8 microU/ml to peak levels of 58 +/- 11 microU/ml. After glucose ingestion, with CCK infused at 24 pmol/kg per h, plasma CCK levels increased to 8 pM and the gastric emptying t1/2 increased to 148 +/- 16 min. In concert with this delay in gastric emptying, peak glucose levels rose to only 129 +/- 17 mg% and peak insulin levels rose to only 24.2 +/- 4.2 microU/ml. With CCK at 12 pmol/kg per h, similar but less dramatic changes were seen. To demonstrate that endogenous CCK could modify the plasma glucose and insulin responses to oral glucose, oral glucose was given with 50 g of lipid containing long-chain triglycerides. This lipid increased peak CCK levels to 3.7 +/- 0.9 pM. Concomitant with this rise in CCK was a delay in gastric emptying and a lowering of plasma glucose and insulin values. To confirm that CCK reduced hyperglycemia by its effect on gastric motility, 36 g glucose was perfused directly into the duodenum through a nasal-duodenal feeding tube in four subjects. With duodenal perfusion of glucose, there was no change in plasma CCK levels, but plasma glucose levels increased from basal levels of 93+/-5 to 148+/-6 mg/dl and insulin levels rose from 10.6+/-3.5 to 29.5+/-5.2 microU/ml. When CCK was infused at 24 pmol/kg per h, neither the plasma glucose nor insulin responses to the duodenal administration of glucose were modified. Thus we conclude that CCK, in physiological concentrations, delays gastric emptying, slows the delivery of glucose to the duodenum, and reduces postprandial hyperglycemia. These data indicate, therefore, that CCK has a significant role in regulating glucose homeostasis in human.

Management of Diabetes and Hyperglycemia in the Hospital: A Practical Guide to Subcutaneous Insulin Use in the Non-Critically Ill, Adult Patient

5 MedStar Diabetes Institute, Washington, DC. R ecently, there has been a heightened interest in improving the quality and safety of the management of diabetes and hyperglycemia in the hospital. While observational data strongly suggests an association of hyperglycemia with morbidity and mortality in adults on general medicine and surgery units, clinical research has not yet defined the best practices for managing hyperglycemia in the hospital outside the intensive care unit (ICU). As a result, many physicians do not have a well-formulated approach to managing hyperglycemia in the noncritically ill hospital patient, and the use of insulin therapy to attain targeted blood glucose (BG) control is often subject to practice variability, leading to suboptimal glycemic outcomes. Practical ‘‘guidelines’’ for the management of this common clinical problem have been formulated by experts in the field, based on understanding of the physiology of glucose and insulin dynamics, the characteristics of currently available insulin preparations, and clinical experience. In 2004, in Clement et al., the American Diabetes Association published a technical review promoting the use of physiologic (‘‘basal-nutritional-correction dose’’) insulin regimens in the hospital to achieve targeted glycemic outcomes. This approach has been disseminated via review articles, and more recently, a randomized, controlled trial demonstrated that hospitalized type 2 diabetes patients experienced better glycemic control when treated with a physiologic insulin regimen than when treated with sliding-scale insulin alone. The Society of Hospital Medicine has assembled a Glycemic Control Task Force, which is charged with providing physicians and hospitals with practical tools to improve the safety and efficacy of diabetes management in the hospital. One product of this work is an educational module that serves as a tutorial on the best practice for the management of diabetes and hyperglycemia in the noncritically ill hospital patient. This article is based on that module, and provides a practical summary of the key concepts that will allow clinicians to confidently employ physiologic insulin regimens when caring for their hospital patients. Case: Ms. X is a 56-year-old obese woman with type 2 diabetes mellitus who is admitted for treatment of an infected diabetes-related foot ulcer. The patient will be allowed to eat dinner in a couple of hours, but the surgeons have requested that she be kept ‘‘nothing by mouth’’ (NPO) after midnight for surgical debridement in the morning. Her current weight is 100 kg, and her No honoraria were paid to any authors for time and expertise spent on the writing of this article.

Glucose delivery — A clarification of its role in regulating glucose uptake in rat skeletal muscle

Abstract The effect of glucose delivery on glucose uptake by muscle is examined by use of various flow rates and infusate glucose concentrations in noncyclically perfused rat hindlimbs. Muscle glucose uptake is found to correlate directly with glucose delivery.

The Mechanism of Action of Estrogen in Castration-Resistant Prostate Cancer: Clues From Hormone Levels

BACKGROUND Estrogen therapy plays a role in the management of castration-resistant prostate cancer (CRPC), although the mechanism of action is not fully known. This current analysis reports the relationship of change in adrenal androgen levels and prostate-specific antigen (PSA) response in patients with CRPC treated with estrogen therapy. PATIENTS AND METHODS Hormone levels were measured for patients with CRPC treated in a multicenter phase II trial of 2 estrogen-containing compounds, the herbal supplement PC-SPES and diethylstilbestrol (DES), with known efficacy in CRPC. Patients with castrate levels of testosterone were randomized to initially receive either PC-SPES 960 mg t.i.d. or DES 3 mg/day. Levels of testosterone, dihydrotestosterone (DHT), estradiol, estrone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione were obtained at baseline and at 12-week intervals until disease progression. Hormone levels were obtained for 38 patients, 20 treated with PC-SPES and 18 treated with DES. RESULTS Significant declines between baseline and 12 weeks of treatment were observed in levels of serum testosterone (P < .001), estrone (P = .02), and DHEA (P < .001). The percent changes at 12 weeks in these hormone levels were inversely proportional to baseline values as measured by Spearmans rank correlation (testosterone: -0.41, P = .01; estrone: -0.64, P = .0001; DHEA: -0.39, P = .02). Levels of SHBG increased in almost all of the patients (97%), with a median percent increase of > 5-fold (P < .0001). Of the 38 evaluable patients, 15 (39% [95% CI, 24%-57%]) experienced a > 50% decline in PSA level. There was no significant difference between treatment groups or between responders and nonresponders in baseline distributions for any of the hormones. At follow-up, 73% of the responders had a decline in the level of DHEA-S compared with 41% of the nonresponders, resulting in a difference in the distribution of the percent change between the subsets (Mann-Whitney test: P = .03). Conversely, 64% of the responders compared with 30% of the nonresponders experienced an increase in DHT, with differing distributions of percent change (P = .02). CONCLUSION Androgens decline in response to estrogen therapy. A decline in DHEA-S and a rise in DHT are both associated with a decline in PSA while patients receive estrogen therapy.

Round Table Discussion on Inpatient Use of Continuous Glucose Monitoring at the International Hospital Diabetes Meeting

In May 2015 the Diabetes Technology Society convened a panel of 27 experts in hospital medicine and endocrinology to discuss the current and potential future roles of continuous glucose monitoring (CGM) in delivering optimum health care to hospitalized patients in the United States. The panel focused on 3 potential settings for CGM in the hospital, including (1) the intensive care unit (ICU), (2) non-ICU, and (3) continuation of use of home CGM in the hospital. The group reviewed barriers to use and solutions to overcome the barriers. They concluded that CGM has the potential to improve the quality of patient care and can provide useful information to help health care providers learn more about glucose management. Widespread adoption of CGM by hospitals, however, has been limited by added costs and insufficient outcome data.In May 2015 the Diabetes Technology Society convened a panel of 27 experts in hospital medicine and endocrinology to discuss the current and potential future roles of continuous glucose monitoring (CGM) in delivering optimum health care to hospitalized patients in the United States. The panel focused on 3 potential settings for CGM in the hospital, including (1) the intensive care unit (ICU), (2) non-ICU, and (3) continuation of use of home CGM in the hospital. The group reviewed barriers to use and solutions to overcome the barriers. They concluded that CGM has the potential to improve the quality of patient care and can provide useful information to help health care providers learn more about glucose management. Widespread adoption of CGM by hospitals, however, has been limited by added costs and insufficient outcome data.

Consensus Statement on Inpatient Use of Continuous Glucose Monitoring

In June 2016, Diabetes Technology Society convened a panel of US experts in inpatient diabetes management to discuss the current and potential role of continuous glucose monitoring (CGM) in the hospital. This discussion combined with a literature review was a follow-up to a meeting, which took place in May 2015. The panel reviewed evidence on use of CGM in 3 potential inpatient scenarios: (1) the intensive care unit (ICU), (2) non-ICU, and (3) transitioning outpatient CGM use into the hospital setting. Panel members agreed that data from limited studies and theoretical considerations suggested that use of CGM in the hospital had the potential to improve patient clinical outcomes, and in particular reduction of hypoglycemia. Panel members discussed barriers to widespread adoption of CGM, which patients would benefit most from use of this technology, and what type of outcome studies are needed to guide use of CGM in the inpatient setting.

Frequently Repeated Glucose Measurements Overestimate the Incidence of Inpatient Hypoglycemia and Severe Hyperglycemia

Objective: The aim was to determine if frequently repeated glucose measurements mandated by an inpatient protocol led to falsely elevated reported rates of both hypo- and hyperglycemia. Methods: In our academic medical center, a mandatory standardized subcutaneous insulin order form and protocol was implemented in May 2006. We analyzed point-of-care blood glucose (BG) measurements collected on all medical/surgical wards during the month of August in both 2005 and 2006 by all BGs measured, by patient admission, and by monitored patient-day. We then repeated all analyses using an algorithm that excluded BG values if another BG was measured less than 5 minutes later or 5–60 minutes earlier. Results: In 2005 versus 2006, there were 7034 versus 8016 glucoses measured in 397 versus 389 patients over 1704 versus 1710 patient days, respectively. Analyses based on patient-day balanced differences in BG measurement frequency and patient length of stay. In both years, failure to exclude repeat values overestimated both the proportion of patient days with hypoglycemia (3.5% versus 1.8% in 2005, p = .003; 2.6% versus 1.3% in 2006, p = .007) and severe hyperglycemia (9.3% versus 7.4% in 2005, p = .09; 7.7% versus 5.9% in 2006, p = .08). Mean, median, and proportion of patient-day means within our target range (80–150 mg/dl) were not significantly different. Conclusions: Glucometric reports should exclude repeated BG measurements from a single clinical episode of hypo- or hyperglycemia in order to accurately reflect inpatient glycemic control.

Case Report: Inadvertent Sulfonylurea Overdosage and Hypoglycemia in an Elderly Woman: Failure of Serum Hypoglycemia Screening

We report a case of an 82 year-old woman who had two episodes of documented hypoglycemia. Initial laboratory testing revealed hyperinsulinemia and a negative serum sulfonylurea screen. While these data suggested the presence of an insulinoma, further evaluation of the case revealed inadvertent ingestion of glimepiride, a sulfonylurea not included in the standard serum sulfonylurea screen.

A detailed description of the implementation of inpatient insulin orders with a commercial electronic health record system.

Background: In the setting of Meaningful Use laws and professional society guidelines, hospitals are rapidly implementing electronic glycemic management order sets. There are a number of best practices established in the literature for glycemic management protocols and programs. We believe that this is the first published account of the detailed steps to be taken to design, implement, and optimize glycemic management protocols in a commercial computerized provider order entry (CPOE) system. Process: Prior to CPOE implementation, our hospital already had a mature glycemic management program. To transition to CPOE, we underwent the following 4 steps: (1) preparation and requirements gathering, (2) design and build, (3) implementation and dissemination, and (4) optimization. These steps required more than 2 years of coordinated work between physicians, nurses, pharmacists, and programmers. With the move to CPOE, our complex glycemic management order sets were successfully implemented without any significant interruptions in care. With feedback from users, we have continued to refine the order sets, and this remains an ongoing process. Conclusions: Successful implementation of glycemic management protocols in CPOE is dependent on broad stakeholder input and buy-in. When using a commercial CPOE system, there may be limitations of the system, necessitating workarounds. There should be an upfront plan to apply resources for continuous process improvement and optimization after implementation.

Falsely Decreased HbA1c in a Type 2 Diabetic Patient Treated with Dapsone

OBJECTIVE To discuss a case of a falsely low hemoglobin A1c (HbA1c) in a transplant patient treated with dapsone and its implications. HbA1c is widely used as a measure of glycemic control in diabetic patients. With the increasing transplant population, it is important to be mindful of medications used in this population that can affect HbA1c and to use other measures of glycemic control to guide treatment decisions. METHODS We present details of the case and review the relevant literature. RESULTS A 61-year-old patient received a liver transplant in 2012 and subsequently was noted to have a falling HbA1c despite evidence of hyperglycemia based on fingerstick glucose and fructosamine measurements. Review of the medical records revealed that the discordance between HbA1c and fingerstick glucose levels developed after initiation of dapsone therapy. Dapsone may lead to a falsely low HbA1c via several mechanisms. Upon cessation of dapsone therapy, the patients HbA1c returned to pre-dapsone levels. CONCLUSION It is important to be aware of medications commonly used in transplant patients that may lead to a falsely low HbA1c level so that incorrect treatment decisions are not made. Fructosamine correlates with HbA1c and can be used as a measure of glycemic control in transplant patients when HbA1c cannot be used.