Normoglycemia In Patients Research Articles

Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy

The role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE.

Cloning a neutral protease of Clostridium histolyticum, determining its substrate specificity, and designing a specific substrate.

Islet transplantation is a prospective treatment for restoring normoglycemia in patients with type 1 diabetes. Islet isolation from pancreases by decomposition with proteolytic enzymes is necessary for transplantation. Two collagenases, collagenase class I (ColG) and collagenase class II (ColH), from Clostridium histolyticum have been used for islet isolation. Neutral proteases have been added to the collagenases for human islet isolation. A neutral protease from C. histolyticum (NP) and thermolysin from Bacillus thermoproteolyicus has been used for the purpose. Thermolysin is an extensively studied enzyme, but NP is not well known. We therefore cloned the gene encoding NP and constructed a Bacillus subtilis overexpression strain. The expressed enzyme was purified, and its substrate specificity was examined. We observed that the substrate specificity of NP was higher than that of thermolysin, and that the protein digestion activities of NP, as determined by colorimetric methods, were lower than those of thermolysin. It seems that decomposition using NP does not negatively affect islets during islet preparation from pancreases. Furthermore, we designed a novel substrate that allows the measurement of NP activity specifically in the enzyme mixture for islet preparation and the culture broth of C. histolyticum. The activity of NP can also be monitored during islet isolation. We hope the purified enzyme and this specific substrate contribute to the optimization of islet isolation from pancreases and that it leads to the success of islet transplantation and the improvement of the quality of life (QOL) for diabetic patients.

Artificial Pancreas Using a Personalized Rule-Based Controller Achieves Overnight Normoglycemia in Patients with Type 1 Diabetes

This study assessed the efficacy of a closed-loop (CL) system consisting of a predictive rule-based algorithm (pRBA) on achieving nocturnal and postprandial normoglycemia in patients with type 1 diabetes mellitus (T1DM). The algorithm is personalized for each patient's data using two different strategies to control nocturnal and postprandial periods. We performed a randomized crossover clinical study in which 10 T1DM patients treated with continuous subcutaneous insulin infusion (CSII) spent two nonconsecutive nights in the research facility: one with their usual CSII pattern (open-loop [OL]) and one controlled by the pRBA (CL). The CL period lasted from 10 p.m. to 10 a.m., including overnight control, and control of breakfast. Venous samples for blood glucose (BG) measurement were collected every 20 min. Time spent in normoglycemia (BG, 3.9-8.0 mmol/L) during the nocturnal period (12 a.m.-8 a.m.), expressed as median (interquartile range), increased from 66.6% (8.3-75%) with OL to 95.8% (73-100%) using the CL algorithm (P<0.05). Median time in hypoglycemia (BG, <3.9 mmol/L) was reduced from 4.2% (0-21%) in the OL night to 0.0% (0.0-0.0%) in the CL night (P<0.05). Nine hypoglycemic events (<3.9 mmol/L) were recorded with OL compared with one using CL. The postprandial glycemic excursion was not lower when the CL system was used in comparison with conventional preprandial bolus: time in target (3.9-10.0 mmol/L) 58.3% (29.1-87.5%) versus 50.0% (50-100%). A highly precise personalized pRBA obtains nocturnal normoglycemia, without significant hypoglycemia, in T1DM patients. There appears to be no clear benefit of CL over prandial bolus on the postprandial glycemia.

Microwell Scaffolds for the Extrahepatic Transplantation of Islets of Langerhans

Allogeneic islet transplantation into the liver has the potential to restore normoglycemia in patients with type 1 diabetes. However, the suboptimal microenvironment for islets in the liver is likely to be involved in the progressive islet dysfunction that is often observed post-transplantation. This study validates a novel microwell scaffold platform to be used for the extrahepatic transplantation of islet of Langerhans. Scaffolds were fabricated from either a thin polymer film or an electrospun mesh of poly(ethylene oxide terephthalate)-poly(butylene terephthalate) (PEOT/PBT) block copolymer (composition: 4000PEOT30PBT70) and were imprinted with microwells, ∼400 µm in diameter and ∼350 µm in depth. The water contact angle and water uptake were 39±2° and 52.1±4.0 wt%, respectively. The glucose flux through electrospun scaffolds was three times higher than for thin film scaffolds, indicating enhanced nutrient diffusion. Human islets cultured in microwell scaffolds for seven days showed insulin release and insulin content comparable to those of free-floating control islets. Islet morphology and insulin and glucagon expression were maintained during culture in the microwell scaffolds. Our results indicate that the microwell scaffold platform prevents islet aggregation by confinement of individual islets in separate microwells, preserves the islet’s native rounded morphology, and provides a protective environment without impairing islet functionality, making it a promising platform for use in extrahepatic islet transplantation.

Factors Expressed by Murine Embryonic Pancreatic Mesenchyme Enhance Generation of Insulin-Producing Cells From hESCs

Islet transplantation has proven to be a successful strategy to restore normoglycemia in patients with type 1 diabetes (T1D). However, the dearth of cadaveric islets available for transplantation hampers the widespread application of this treatment option. Although human embryonic stem cells and induced pluripotent stem cells are capable of generating insulin-producing cells in vitro when provided with the appropriate inductive cues, the insulin-expressing cells that develop behave more like immature β-cells with minimal sensitivity to glucose stimulation. Here, we identify a set of signaling factors expressed in mouse embryonic mesenchyme during the time when foregut and pancreatic progenitors are specified and test their activities during in vitro differentiation of human embryonic stem cells. Several of the identified factors work in concert to expand the pancreatic progenitor pool. Interestingly, transforming growth factor (TGF)-β ligands, most potent in inducing pancreatic progenitors, display strong inhibitory effects on subsequent endocrine cell differentiation. Treatment with TGF-β ligands, followed by the addition of a TGF-β receptor antagonist, dramatically increased the number of insulin-producing cells in vitro, demonstrating the need for dynamic temporal regulation of TGF-β signaling during in vitro differentiation. These studies illustrate the need to precisely mimic the in vivo conditions to fully recapitulate pancreatic lineage specification in vitro.

Gene Therapy for Type 1 Diabetes Moves a Step Closer to Reality

The prevalence of diabetes mellitus (DM) is assuming pandemic proportions and is currently estimated at 285 million cases (1). Although most cases are due to obesity-associated type 2 DM, there is also an increase in the annual prevalence of type 1 DM (2). It is estimated that 10% of the diabetic population have type 1 DM. Both forms of DM are associated with a long-term risk of microvascular and macrovascular complications (3) and the immediate risk of hypoglycemia. There is abundant evidence that attainment of near normoglycemia will reduce the risk of complications associated with DM (4). However, attainment of near normoglycemia in patients with type 1 DM is limited by the occurrence of hypoglycemia. Patients with hypoglycemic unawareness are particularly prone to this problem as a limiting factor for achieving the required glycemic control. DM clinics globally have many patients with type 1 DM in whom recurrent hypoglycemia and the phenomenon of hypoglycemic unawareness present major clinical problems. Fortunately, there are many promising and exciting advances on the horizon for patients with this problem, including gene therapy as reported in this issue of Diabetes by Bosch and colleagues (5). In the current study, the authors use an adeno-associated viral (AAV) vector to overexpress the genes for insulin and glucokinase in skeletal muscle in a canine model of DM. The study addresses the question of …

A Theranostic Small Interfering RNA Nanoprobe Protects Pancreatic Islet Grafts From Adoptively Transferred Immune Rejection

Islet transplantation has recently emerged as an acceptable clinical modality for restoring normoglycemia in patients with type 1 diabetes mellitus (T1DM). The long-term survival and function of islet grafts is compromised by immune rejection–related factors. Downregulation of factors that mediate immune rejection using RNA interference holds promise for improving islet graft resistance to damaging factors after transplantation. Here, we used a dual-purpose therapy/imaging small interfering (si)RNA magnetic nanoparticle (MN) probe that targets β2 microglobulin (B2M), a key component of the major histocompatibility class I complex (MHC I). In addition to serving as a siRNA carrier, this MN-siB2M probe enables monitoring of graft persistence noninvasively using magnetic resonance imaging (MRI). Human islets labeled with these MNs before transplantation into B2M (null) NOD/scid mice showed significantly improved preservation of graft volume starting at 2 weeks, as determined by longitudinal MRI in an adoptive transfer model (P < 0.05). Furthermore, animals transplanted with MN-siB2M–labeled islets demonstrated a significant delay of up to 23.8 ± 4.8 days in diabetes onset after the adoptive transfer of T cells relative to 6.5 ± 4.5 days in controls. This study demonstrated that our approach could protect pancreatic islet grafts from immune rejection and could potentially be applied to allotransplantation and prevention of the autoimmune recurrence of T1DM in islet transplantation or endogenous islets.

Does Response of RAS Blockade on Serum K+ Levels Influence Its Glycemic‐Mitigating Response When Combined With Hydrochlorothiazide?

The authors previously reported that addition of valsartan ameliorated the negative metabolic effects of hydrochlorothiazide in obese hypertensive patients through an enhanced postprandial insulin response. In this secondary analysis, the authors tested whether this enhanced insulin response to valsartan/hydrochlorothiazide was influenced by serum potassium levels, which were reduced to a lesser extent, when compared with amlodipine/hydrochlorothiazide. Results showed that the early insulin response with valsartan plus hydrochlorothiazide occurred regardless of serum potassium levels. Heightened insulin response was, however, not significantly different when patients with normal potassium (>3.9 mEq/L) at baseline and low potassium (≤3.9 mEq/L) at the end of the study were compared with the amlodipine/hydrochlorothiazide group. Despite the influence of serum potassium on insulin secretory response to a glucose challenge, the addition of valsartan maintained normoglycemia in patients given hydrochlorothiazide. Thus, the metabolic response to hydrochlorothiazide was improved with addition of valsartan through an enhanced insulin response that was not greatly affected by changes in potassium levels.

Long-term outcome after pancreas transplantation

Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the very important risk factors for short-term survival of a pancreas transplant, there is not a lot of information available about factors that distinguish short-term from long-term graft function. The analysis of 18,159 pancreas transplants from the International Pancreas Transplant Registry, performed from 25 July 1978 to 31 December 2005, showed an improvement not only in short-term but also in long-term graft function. Most recent 5-year, 10-year and 20-year graft function for transplants with the appropriate follow-up time showed 80, 68 and 45%, respectively, for simultaneous pancreas/kidney transplants; 62, 46 and 16%, respectively, for pancreas after kidney; and 59, 39 and 12%, respectively, for pancreas transplants alone. Important factors influencing long-term function were factors that described the quality of the deceased donor. Pancreas transplants in younger or African-American recipients showed a higher risk of graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants. With a careful donor selection, not only short-term but also long-term pancreas graft function and, therefore, good metabolic control can be achieved for the diabetic patient.

PS18 - 88. Expansion of human beta cell progenitors using a three-dimensional culture system

Beta cell replacement therapy is an attractive option to achieve normoglycemia in patients with type 1 diabetes. However, future implementation for larger groups of patients is hampered by the lack of donor organs.

Perioperative Glucose and Insulin Administration While Maintaining Normoglycemia (GIN Therapy) in Patients Undergoing Major Liver Resection

Although hyperglycemia is a well-recognized risk factor in the context of cardiac surgery, the relevance of perioperative glycemic control for patients undergoing major noncardiac operations has received little attention. We designed this study to assess the hyperglycemic response to liver resection, and to test the hypothesis that perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) provides glycemic control superior to that achieved by the conventional use of insulin. Patients were randomly assigned to GIN therapy or standard therapy (control group). In the GIN therapy group, insulin was administered at 2 mU . kg(-1) . min(-1) during surgery. At the end of surgery, the insulin infusion was decreased to 1 mU . kg(-1) . min(-1) and continued for 24 hours. Dextrose 20% was infused at a rate adjusted to maintain blood glucose within the target range of 3.5 to 6.1 mmol . L(-1) (63-110 mg . dL(-1)). Patients in the standard therapy group received a conventional insulin sliding scale during and after surgery. The mean and SD of blood glucose as well as the percentage of blood glucose values within the target range were calculated. To evaluate intrasubject variability, the coefficient of variability (CV) of blood glucose was calculated for each patient. Episodes of severe hypoglycemia, i.e., blood glucose <2.2 mmol . L(-1) (40 mg . dL(-1)), were recorded. The primary outcome was the proportion of normoglycemic measurements. We studied 52 patients. The mean blood glucose value in patients receiving GIN therapy always remained within the target range. The blood glucose levels were lower in the GIN therapy group than in the standard therapy group (during surgery, P < 0.01; after surgery, P < 0.001). In nondiabetic patients receiving GIN therapy (n = 19), target glycemia was achieved in 90.1% of the blood glucose measurements during surgery and in 77.8% of the measurements after surgery. In diabetic patients receiving GIN therapy (n = 7), target glycemia was achieved in 81.2% of the blood glucose measurements during surgery and in 70.5% of the measurements after surgery. In nondiabetic patients receiving standard therapy (n = 19), target glycemia was achieved in 37.4% of the blood glucose measurements during surgery and in 18.3% of the measurements after surgery. In diabetic patients receiving standard therapy (n = 7), target glycemia was achieved in 4.3% of the blood glucose measurements during surgery and in 2.9% of the measurements after surgery. The SD and CV of blood glucose were smaller in the GIN therapy group than in the standard therapy group, especially in nondiabetic patients after surgery (SD, P < 0.001; CV, P = 0.027). No patients receiving GIN therapy experienced severe hypoglycemia during surgery. One patient receiving GIN therapy experienced hypoglycemia in the intensive care unit after surgery without neurological sequelae. GIN therapy effectively provides normoglycemia in patients undergoing liver resection (clinicaltrials.gov, NCT00774098).

Pancreas transplantation in the United States: a review

The goal of pancreas transplantation is to restore normoglycemia in patients with labile diabetes. The results of this procedure improved over the years, but, although pancreas transplantation is not considered experimental anymore, there is often reluctance to recommend this procedure because of the complexity, especially for solitary pancreas transplants. This article reviews the current status of pancreas transplantation. Many improvements have been made in the surgical techniques and immunosuppressive regimens. The overall rate of technical problems decreased, yet immunologic graft loss is still a problem in solitary pancreas transplants. Careful donor selection significantly decreased the risk of graft failure and therefore improved patient survival. With modern immunosuppressive protocols and careful donor selection, patient survival rates and pancreas transplant graft function can be further improved in all three pancreas transplant categories.

Perioperative tight glucose control with hyperinsulinemic-normoglycemic clamp technique in cardiac surgery

Objective Previous attempts to achieve tight glucose control in surgical patients were associated with a significant incidence of hypoglycemia. The purpose of this study was to evaluate the efficacy of perioperative glucose and insulin administration while maintaining normoglycemia using a hyperinsulinemic-normoglycemic clamp technique. Methods We studied 70 non-diabetic and 40 diabetic patients undergoing cardiac procedures. Before induction of anesthesia, insulin was administered at 5 mU · kg −1 · min −1. Blood glucose (BG) concentrations were determined every 15–30 min. Dextrose 20% was infused at a rate adjusted to maintain BG within 3.5–6.1 mmol/L. At the end of surgery, insulin infusion was decreased to 1 mU · kg −1 · min −1 and continued for 24 h. The mean ± standard deviation of BG and the percentage of BG values within the target range were calculated perioperatively. Episodes of severe hypoglycemia, i.e., BG <2.2 mmol/L, were recorded. Results The mean BG remained within target at all times. Normoglycemia in non-diabetic patients was achieved in 92.8% of measurements during and in 83.2% after surgery. In diabetic patients 87.4% of values were within target intraoperatively and 76.7% after surgery. The rate of severe hypoglycemia was 2.7% (three patients). In non-diabetic patients the incidence of severe hypoglycemia was 0.2% of measurements during and 0.1% after surgery. Diabetic patients showed only one episode of severe hypoglycemia after surgery (0.1%). Conclusion Perioperative use of a hyperinsulinemic-normoglycemic clamp technique established and maintained normoglycemia in patients undergoing cardiac surgery with little risk of hypoglycemia.

Increased blood flow by insulin infusion targeting normoglycemia in patients with severe sepsis: friend or foe?

A small study in patients with severe sepsis suggested that insulin infused to normalize blood glucose levels increased forearm flow. This clinical observation supports the effect of insulin on the endothelium, as previously shown by in vitro studies and by in vivo animal models of critical illness, but the clinical consequences remain unclear.

Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules

Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-β, Ad.CTLA4-Ig, or Ad.TNF-α after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74 ± 19 ng, 50 ± 4 ng, 821 ± 31 ng, and 77 ± 18 ng/100 islets, respectively. Transplantation of IL-12p40, TNF-α, and CTLA4-Ig but not TGF-β-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-α and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-α-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-α and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice.

A review of the use of insulin protocols to maintain normoglycaemia in high dependency patients

This paper critically examines the evidence base for and issues involved in the introduction of an insulin protocol to maintain normoglycaemia in patients within a medical/surgical high dependency ward. A growing body of evidence has linked hyperglycaemia to worsened clinical outcomes. This has led to intravenous insulin protocols becoming a new standard of care in intensive care units. However, the use and benefits of insulin protocols within high dependency units have not yet been addressed in the literature. The literature was examined for the 10-year period up to January 2005. The databases searched were MEDLINE, OVID, CINHAL, the British Nursing Index, the EBSCO collection, the COCHRANE library, the Department of Health, and guidelines within the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence using the key words insulin, protocol, hyperglycaemia, critical care, intensive care and high dependency. The literature reports that both medical and surgical intensive care patients treated with intravenous insulin protocols to maintain normoglycaemia experienced significantly reduced mortality and morbidity. Resulting hypoglycaemic episodes were limited with no incidence of patient deterioration. A review of published intravenous insulin protocols used in intensive care settings revealed their safe and effective use in nurse to patient ratios similar to those present in high dependency units. In the light of this evidence, it would seem safe and ethically correct to enable high dependency patients to benefit from this cheap intervention. An insulin protocol tailored for the glycaemic control of high dependency patients has been suggested, although it may have to be commenced in conjunction with other fluid and nutrition protocols to safeguard the risk of hypoglycaemic events. Further research into the safety and benefit of insulin protocols in high dependency populations is required. The stress of critical illness often leads to hyperglycaemia, which is linked to worsened clinical outcomes. Both medical and surgical intensive care patients treated with intravenous insulin protocols to maintain normoglycaemia experienced significantly reduced mortality and morbidity. This paper identifies that, to date, no research into the benefits of glycaemic control in high dependency populations has been published. The case for the introduction of insulin protocols into high dependency units is therefore examined and an insulin protocol suggested.

P1152 APPLICATION OF AN ALPHA-GLUCOSIDASE INHIBITOR IN THE TREATMENT OF GLYCOGEN STORAGE DISEASE TYPE 1. A FEASIBILITY STUDY IN HEALTHY SUBJECTS.

Introduction: Uncooked cornstarch (UCCS) is widely used to maintain normoglycemia in patients with glycogen storage disease type 1 (GSD1). However, compliance of the UCCS treatment is suboptimal because of the unpleasant taste of the UCCS. Acarbose, an alpha-glucosidase inhibitor supposed to delay carbohydrate digestion, added to a carbohydrate rich meal, might be an alternative approach in the treatment of GSD1. A cross-over study in healthy subjects was conducted to investigate the feasibility to apply an alpha-glucosidase inhibitor in the treatment of GSD1. This study compared the absorption profile after ingestion of UCCS with that after ingestion of corn pasta with acarbose. Methods: Seven healthy male volunteers (age: 23 ± 1 (mean ± SE) years, BMI 22 ± 1.1 kg/m2) ingested at least one week apart UCCS in 250 ml water or corn pasta with 12.5 mg of acarbose (CPac). Both test meals contained an equivalent of 50 g of glucose and were naturally enriched with 13C. During the 6 hours following consumption of the test meals plasma glucose and insulin were monitored. Using a primed continuous infusion of D-[6,6-2H2]glucose, the systemic appearance of exogenous glucose (RaE) was estimated, which reflects the intestinal carbohydrate absorption. Results: Significant higher total glucose responses were observed between 60 and 150 min after consumption of UCCS compared to CPac (p<0.04). Insulin responses between 60 and 240 min were significantly higher after ingestion of UCCS than those after ingestion of CPac (p<0.03). In the fasting state, before ingestion of the test meals, the endogenous glucose production was 2.24 ± 0.09 mg/kg/min. Between 30–180 min the mean RaE after consumption of UCCS (2.27 ± 0.24 mg/kg/min) was significantly higher than the mean RaE of CPac (1.16 ± 0.14 mg/kg/min)(p<0.02). Six hours after ingestion of UCCS the recovery of glucose was significantly higher than after ingestion of CPac (88 ± 6% and 45 ± 4% of the administered dose respectively, p<0.02). Conclusion: After ingestion of UCCS the mean RaE between 30 and 180 min equals the rate of endogenous glucose production. Addition of 12.5 mg of acarbose to corn pasta does not result in an absorption profile able to provide for the glucose requirements. The low 6 hours recovery of glucose after ingestion of CPac (45%) indicates that the digestion of corn pasta is inhibited to some extent. Acarbose applied in combination with the amount and type of carbohydrate used in this study is not a suitable alternative in the treatment of GSD1.

Attempting to Maintain Normoglycemia During Cardiopulmonary Bypass with Insulin May Initiate Postoperative Hypoglycemia

We attempted to develop an insulin administration protocol that maintains normoglycemia in patients undergoing cardiac surgery and to study the effects of intraoperative blood glucose management on serum levels of creatine phosphokinase isoenzyme BB (CK-BB) and S-100 protein. Twenty nondiabetic patients were randomly allocated to receive either “tight control” of blood glucose with a standardized IV insulin infusion intraoperatively (Group TC) or “no control” of blood glucose intraoperatively (Group NC). Perioperative serum levels of glucose, CK-BB, and S-100 protein were determined in all patients. Group TC patients received 90.0 ± 49.2 units of insulin, whereas Group NC patients received none. Despite insulin, both Group TC (P = 0.00026) and Group NC (P = 0.00003) experienced similar significant increases in blood glucose levels during hypothermic cardiopulmonary bypass. However, mean blood glucose level upon intensive care unit arrival was significantly decreased in Group TC, compared with Group NC (84.7 ± 41.0 mg/dL, range 32–137 mg/dL vs 201.4 ± 67.5 mg/dL, range 82–277 mg/dL, respectively; P = 0.0002). Forty percent of Group TC patients required treatment for postoperative hypoglycemia (blood glucose level <60 mg/dL). Substantial interindividual variability existed in regard to insulin resistance. The investigation was terminated after we realized that normoglycemia was unattainable with the study protocol and that postoperative hypoglycemia was unpredictable. All patients in both groups experienced similar significant increases in postoperative serum levels of CK-BB and S-100 protein. These results indicate that “tight control” of intraoperative blood glucose in nondiabetic patients undergoing cardiac surgery was unattainable with the study protocol and may initiate postoperative hypoglycemia. Implications: The appropriate intraoperative management of hyperglycemia and whether it adversely affects neurologic outcome in patients after cardiac surgery remains controversial. This investigation reveals that attempting to maintain normoglycemia in this setting with insulin may initiate postoperative hypoglycemia.

Glucose control guidelines: current concepts

The Diabetes Control and Complications Trial (DCCT) ended decades of controversy regardingthe necessity of tight glycemic control for type 1 diabetes by demonstrating that glucose control using intensive insulin therapy significantly reduced long-term microvascular complications. The American Diabetes Association (ADA) guidelines empirically support the same goal of attempting to obtain normoglycemia in patients with type 2 disease; however, unlike in type 1 disease, insulin is a tertiary option, following diet, exercise, and oral agents. Emerging long-term intervention data in type 2 diabetes suggest that insulin may pose increased cardiovascular risk in this already ‘at-risk’ population. However, many type 2 diabetics will eventually require insulin. Clearly, more studies are warranted to assess the risks, benefits, and feasibility of improved glycemic control in type 2 diabetes. Nonetheless, two principles are clear. First, promoting blood glucose levels approaching normoglycemia is an important factor in preventing longterm microvascular complications. Second, type 2 diabetes comprises numerous metabolic conditions; therefore an integrated effort by the patient and healthcare team is required to optimize blood glucose and serum lipid levels and minimize cardiovascular risk factors.

Prolongation of normoglycemia in patients with type I glycogen storage disease

Prolongation of normoglycemia in patients with type I glycogen storage disease