Spinal anesthesia protects against perioperative hyperglycemia in patients undergoing hip arthroplasty

Study ObjectiveTo determine whether spinal anesthesia blunts surgical stress reactions and results in less perioperative hyperglycemia.DesignProspective, randomized controlled study.SettingOperating room of a university hospital.Patients68 adult, nondiabetic (n=40) and diabetic (n=28), ASA physical status 1, 2, and 3 patients patients undergoing elective total hip replacement.InterventionsGeneral or spinal anesthesia was administered.MeasurementsBlood HbA1C was measured preoperatively to identify patients with undiagnosed diabetes. Glucose levels were checked preoperatively, then immediately after, and one hour after surgery. A conventional glucose control protocol was used, where insulin was given when blood glucose concentrations exceeded 250 mg/dL.Main ResultsPreoperative glucose levels in general and spinal anesthesia patients were comparable and not significantly different in nondiabetic and diabetic patients. At the end of surgery and one hour after surgery, glucose levels were significantly higher in patients undergoing general anesthesia compared with baseline values in both diabetic and nondiabetic patients (P < 0.05). In nondiabetic and diabetic patients, a significant increase in glucose level was found in patients undergoing general anesthesia versus spinal anesthesia (P < 0.05). In patients receiving spinal anesthesia, glucose levels remained stable. Two diabetic patients undergoing general anesthesia received insulin.ConclusionSpinal anesthesia attenuates the hyperglycemic response to surgical stimuli in diabetics and nondiabetic patients.     

Hydrogen sulfide attenuates lung ischemia–reperfusion injury through SIRT3-dependent regulation of mitochondrial function in type 2 diabetic rats

BackgroundLung ischemia–reperfusion injury is a complex pathophysiologic process associated with high morbidity and mortality. We have demonstrated elsewhere that diabetes mellitus aggravated ischemia-induced lung injury. Oxidative stress and mitochondrial dysfunction are drivers of diabetic lung ischemia-reperfusion injury; however, the pathways that mediate these events are unexplored. In this study using a high-fat diet–fed model of streptozotocin-induced type 2 diabetes in rats, we determined the effect of hydrogen sulfide on lung ischemia-reperfusion injury with a focus on Sirtuin3 signaling.MethodsRats with type 2 diabetes were exposed to GYY4137, a slow release donor of hydrogen sulfide with or without administration of the Sirtuin3 short hairpin ribonucleic acid plasmid, and then subjected to a surgical model of ischemia–reperfusion injury of the lung (n = 8). Lung function, oxidative stress, inflammation, cell apoptosis, and mitochondrial function were measured.ResultsCompared with nondiabetic rats, animals with type 2 diabetes at baseline exhibited significantly decreased Sirtuin3 signaling in lung tissue and increased oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction (P < .05 each). In addition, further impairment in Sirtuin3 signaling was found in diabetic rats subjected to this model of lung ischemia–reperfusion. Simultaneously, the indexes showed further aggravation. Treatment with hydrogen sulfide restored Sirtuin3 expression and decreased lung ischemia–reperfusion injury in animals with type 2 diabetes mellitus by improving lung functional recovery, decreasing oxidative damage, suppressing inflammation, ameliorating cell apoptosis, and preserving mitochondrial function (P < .05). Conversely, these protective effects were largely reversed in Sirtuin3 knockdown rats.ConclusionImpaired lung Sirtuin3 signaling associated with type 2 diabetic conditions was further attenuated by an ischemia-reperfusion insult. Hydrogen sulfide ameliorated reperfusion-induced oxidative stress and mitochondrial dysfunction via activation of Sirtuin3 signaling, thereby decreasing lung ischemia-reperfusion damage in rats with a model of type II diabetes.     

Weight loss and changes in use of antidiabetic medication in obese type 2 diabetics after laparoscopic gastric banding

BackgroundInterest in bariatric surgery is growing as an effective method for long-term metabolic control in morbidly obese patients with type 2 diabetes. We analyzed the weight loss and changes in use of diabetic medication in obese patients with type 2 diabetes treated with laparoscopic adjustable gastric banding (LAGB).MethodsFrom 1993 to 2005, 1791 morbid obese patients underwent LAGB at our institution. Of the 1791 patients, 394 (22%) had type 2 diabetes mellitus at baseline. Of the 394 patients with diabetes, 52 were receiving diabetic medication. The median follow-up period for the drug-treated diabetic patients was 3 years (range .25–9).ResultsThe drug-treated diabetic patients were older (age 47.6 ± 7.5 versus 37.5 ± 10.7 years, P <.001), weighed more (body mass index 49.1 ± 9.5 versus 45.6 ± 7.5 kg/m², P 0.001), and were more frequently affected by co-morbidities than the nondiabetic patients at surgery. The percentage of excess weight loss 1 year after surgery was less (32.4% ± 14.1% versus 41.1% ± 19.9%, P <.01) for the drug-treated diabetic patients than for the nondiabetic patients. This difference was maintained for 5 years of follow-up. A significant decline occurred in the use of both oral diabetic medication and insulin after surgery. Of the 52 patients treated with oral antidiabetic medication at baseline, 33 required oral antidiabetic medication at the end of follow-up. Of the 6 patients who also required insulin at baseline, 2 did so at the end of follow-up. The use of diabetic medication had increased in 4 patients (7.7%), was unchanged in 12 (23.1%), had decreased in 17 (32.7%), and was suspended in 19 (36.5%) of 52 patients.ConclusionThe amount of weight loss after LAGB was less in drug-treated diabetic patients than in nondiabetic patients. However, LAGB was associated with a sustained reduction in the use of diabetic medication.     

Increased susceptibility to pulmonary infection in alloxan diabetic mice

Pulmonary infections in diabetics have received little attention clinically or experimentally despite an impression that diabetics are more prone to pulmonary infections and do poorly with these and all infections. In a mouse model, aerosolized pneumococci were used in order to mimic the natural portal of entry of pneumococci, to investigate susceptibility to pneumococcal infection in alloxan diabetic and normal mice, and to test the hypothesis that insulin therapy would have a protective effect. When exposed to an aerosol created from 10⁸ type III Streptococcus pneumoniae (PnIII)/ml, nondiabetic mice had a higher survival rate than uncontrolled diabetic mice (P < 0.001) and insulin-treated diabetic mice (P < 0.001). Insulin-treated diabetic mice had a significantly decreased death rate compared to untreated diabetic mice (P < 0.05). The data show that alloxan diabetic mice are more likely to succumb to infection from aerosolized pneumococci than are normal mice. Insulin therapy appeared to decrease this susceptibility. A possible clinical inference is that insulin therapy is beneficial in diabetic patients with pulmonary infections.     

Plasma Osteocalcin Is Inversely Related to Fat Mass and Plasma Glucose in Elderly Swedish Men

The osteoblast‐derived protein osteocalcin has recently been shown to affect adiposity and glucose homeostasis in mice, suggesting that the skeleton influences energy metabolism through an endocrine mechanism. The aim of this study was to investigate the relationship between plasma osteocalcin and parameters reflecting fat mass and glucose homeostasis in humans. Fasting levels of plasma osteocalcin, plasma glucose, serum insulin, and lipids were analyzed in elderly men (75.3 ± 3.2 yr of age) in the Gothenburg part (all subjects, n = 1010; nondiabetic, n = 857; diabetic, n = 153) of the MrOS Sweden study. Fat mass and lean mass were analyzed using DXA. Diabetic subjects had lower plasma osteocalcin (?21.7%, p < 0.001) than nondiabetic subjects. For both all subjects and nondiabetic subjects, plasma osteocalcin was clearly inversely related to body mass index (BMI), fat mass, and plasma glucose (p < 0.001), whereas it was not associated with height or lean mass. Plasma osteocalcin explained a substantial part (6.3%) of the variance in plasma glucose, whereas it associated moderately with serum insulin. Multiple linear regression models adjusting for serum insulin and fat mass showed that plasma osteocalcin was an independent negative predictor of plasma glucose (p < 0.001). We herein, for the first time in humans, show that plasma osteocalcin is inversely related to fat mass and plasma glucose. Although one should be cautious with mechanistic interpretations of cross‐sectional association studies, our human data support recently published experimental studies, showing endocrine functions of osteoblast‐derived osteocalcin on glucose and fat homeostasis.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

Background. Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. Methods. We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. Results. In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5±2.9 and 12.6±2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3±2.3 vs 8.6±1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5±2.1 vs 9.0±2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. Conclusions. Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

The effects of streptozocin-induced diabetes and weight-matched pair feeding on tumor growth and survival in fischer rats

Sixty-one 150- to 180-g Fischer rats were assigned to one of four experimental groups: nondiabetic, tumor bearer (ND-TB, n = 15); diabetic, non-tumor bearer (D-NTB, n = 19); diabetic, tumor bearer (D-TB, n = 16); or nondiabetic, weight-matched control, tumor bearer (WM-TB, n = 11). The WM group was housed in metabolic cages and fed H₂O ad libitum and rat chow to achieve appropriate carcass weight (comparable to D-NTB). Diabetes was induced with a single dose of streptozocin (STZ) 40 mg/kg body wt iv, 10 days prior to tumor inoculation. Viable methylcholanthrene-induced sarcoma cells (1 × 10⁶) were injected into the right flank on Day 0. Body weight and tumor volume were assessed every 3 days. On the day of death, the animal and excised tumor were weighed. Dividing the growth curves versus time into two phases based on tumor volumes 0–20 and 20–60 cm³ defined a significant early growth (0–20 cm³) delay of 5 days in the D-TB and WM groups vs the ND-TB group. The growth rate from 20–60 was not different in any group. Tumor growth retardation seen in STZ-induced diabetic animals can be mimicked and exceeded in a pair-fed, weight-matched control group. Diabetic and starved animals have smaller tumors and live longer than ad lib fed, nondiabetic animals. The delay in tumor growth is a reflection of the retardation in the early (0–20 cm³) growth rate.     

Omentectomy added to Roux-en-Y gastric bypass surgery: a randomized,controlled trial

BackgroundExcess visceral adipose tissue predicts for incipient diabetes mellitus and cardiovascular disease. Human data are mixed regarding the benefits of selective visceral adipose tissue reduction. We investigated the effects of omentectomy added to laparoscopic Roux-en-Y gastric bypass on glucose homeostasis and lipids, inflammatory markers, and adipokines 90 days postoperatively in nondiabetic patients at the Legacy Good Samaritan Hospital and Oregon Health and Science University (Portland, OR).MethodsA single-blind, randomized study of laparoscopic Roux-en-Y gastric bypass plus omentectomy versus laparoscopic Roux-en-Y gastric bypass alone in 28 subjects (7 men and 21 women). The groups were matched at baseline for gender, age, and body mass index (BMI). The eligibility criteria included age ≥18 years, BMI ≥40 and <50 kg/m² without co-morbid conditions or BMI ≥35 and <50 kg/m² with co-morbid conditions. The primary outcome measures were changes in the fasting plasma glucose, insulin, and homostatic model assessment of insulin resistance. The secondary measures were BMI and the high-sensitivity C-reactive protein, tumor necrosis factor-α, interleukin, total and high-molecular-weight adiponectin, fibrinogen, and plasminogen activator inhibitor-1 levels.ResultsAfter surgery, the BMI decreased significantly in both groups and was not different at the follow-up point. Although many outcome parameters improved with weight loss in both groups postoperatively, only the omentectomy group experienced statistically significant decreases in fasting glucose (P < .05), total (P = .004) and very-low-density lipoprotein (P = .001) cholesterol, and an increase in the high-molecular-weight/total adiponectin ratio (P = .013).ConclusionsOmentectomy added to laparoscopic Roux-en-Y gastric bypass results in favorable changes in glucose homeostasis, lipid levels, and adipokine profile at 90 days postoperatively. These data support the hypothesis that selective ablation of visceral adipose tissue conveys metabolic benefits in nondiabetic humans.     

Prostaglandin E1 alleviates neuropathic pain and neural dysfunction from entrapment neuropathy associated with diabetes mellitus

In this report, we present the results of investigation of the effects of prostaglandin E1 (PGE1) on entrapment neuropathy using a diabetic rat. A total of 60 male Sprague‐Dawley rats were used in the study. The model of tibial nerve entrapment neuropathy associated with diabetes mellitus was created by streptozotocin‐induced diabetic rats reared in cages with wire grid flooring. Rats were assigned to four groups: nondiabetic (n = 15), untreated diabetic (n = 15), diabetic treated with 30 μg/kg PGE1 (n = 15), and diabetic treated with 100 μg/kg PGE1 (n = 15). Pain tests and electrophysiological tests were performed at 0, 2, and 4 weeks, and assessments of gait, histology, and mRNA expression levels were performed at 4 weeks after initiating the PGE1 administration. In the 30 and 100 μg groups, the mechanical withdrawal thresholds measured by pain tests at 4 weeks (36.2 ± 16.4 g and 31.7 ± 15.3 g, respectively) and the motor conduction velocity (24.0 ± 0.2 m/s and 24.4 ± 0.3 m/s, respectively) were significantly higher than the untreated diabetic group (all P < 0.05) and lower than the nondiabetic group (all P < 0.001). In the gait analysis, the mean intensities in the 30 and 100 μg group (128.0 ± 20.1 a.u. and 109.0 ± 27.8 a.u., respectively) were significantly higher than the untreated diabetic (P < 0.01) and were not significantly different from the nondiabetic group (P = 0.81). Fiber density (P = 0.46) and fiber diameter (P = 0.15) did not show any significant differences. PGE1 significantly decreased nerve growth factor (NGF) mRNA and increased vascular endothelial growth factor (VEGF) mRNA in the tibial nerve (both P < 0.01). In conclusion, neurological deteriorations of diabetic rats were alleviated with PGE1, which is associated with inhibition of NGF and enhancement of VEGF at the entrapment site. © 2014 Wiley Periodicals, Inc. Microsurgery 34:568–575, 2014.     

The Effect of Dexamethasone on Postoperative Blood Glucose in Patients With Type 2 Diabetes Mellitus Undergoing Total Joint Arthroplasty

BackgroundPerioperative glucocorticoids are routinely administered to patients undergoing total joint arthroplasty (TJA) to decrease postoperative pain and nausea. However, there is concern regarding the effects of glucocorticoids on perioperative glucose control in diabetes. The goal of this study is to determine if administration of preoperative dexamethasone to diabetic patients is significantly associated with hyperglycemia and increased insulin requirements in the immediate postoperative period after TJA and to identify risk factors for postoperative hyperglycemia immediately after TJA.MethodsA retrospective review of type 2 diabetic patients undergoing TJA from 2010 to 2015 (n = 285) was undertaken to evaluate the effect of dexamethasone on postoperative glucose control. Preoperative baseline characteristics were compared between patients who did and did not receive 8 mg of intravenous dexamethasone preoperatively. Postoperative glucose and insulin requirements were evaluated with respect to dexamethasone dosing. Statistical analysis was performed using logistic regression models.ResultsDexamethasone administration did not correlate with the maximum postoperative blood glucose (P = .78). There was a significantly higher initial postoperative blood glucose after intravenous dexamethasone administration (P < .01). Dexamethasone administration was associated with increased aspart insulin requirements on postoperative day 0 (P = .04). However, preoperative hemoglobin A1c was most strongly associated with postoperative glucose control.ConclusionPreoperative dexamethasone administration to diabetic patients was associated with an initial increase in blood glucose and increased insulin requirement on postoperative day 0. Yet the observed effect on glucose control in diabetic patients may not outweigh the known clinical benefits of perioperative glucocorticoids.     

Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience

BackgroundThis study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups.MethodsA total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients.ResultsBaseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040).ConclusionThis study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.     

Interactions Among Glucose Delivery,Transport, and Phosphorylation That Underlie Skeletal Muscle Insulin Resistance in Obesity and Type 2 Diabetes: Studies With Dynamic PET Imaging

Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([¹⁵O]H₂O, [¹¹C]3-O-methylglucose [3-OMG], and [¹⁸F]fluorodeoxyglucose [FDG]) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bidirectional glucose transport, and glucose phosphorylation to interrogate the individual contribution and interaction among these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight nondiabetic subjects (NW) (n = 5), obese nondiabetic subjects (OB) (n = 6), and obese subjects with T2D (n = 7) during fasting conditions and separately during a 6-h euglycemic insulin infusion at 40 mU·m⁻²·min⁻¹. Tissue tracer activities were derived specifically within the soleus muscle with PET images and magnetic resonance imaging. During fasting, NW, OB, and T2D subjects had similar [¹¹C]3-OMG and [¹⁸F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [¹⁸F]FDG uptake by muscle was inversely correlated with systemic IR (P < 0.001). The increase in insulin-stimulated glucose transport was less (P < 0.01) in T2D (twofold) than in NW (sevenfold) or OB (sixfold) subjects. The fractional phosphorylation of [¹⁸F]FDG during insulin infusion was also significantly lower in T2D (P < 0.01). Dynamic triple-tracer PET imaging indicates that skeletal muscle IR in T2D involves a severe impairment of glucose transport and additional impairment in the efficiency of glucose phosphorylation.     

Abnormal cell calcium concentrations in cultured bone cells obtained from femurs of obese and noninsulin-dependent diabetic rats

Summary Cytoplasmic free calcium concentration [Ca²⁺]i was quantified in cultured bone cells with osteoblastic characteristics. The cells were obtained from femurs of obese (fa/fa) Wistar-Kyoto rats, from nonobese, noninsulin-dependent diabetic (NIDD) Sprague Dawley rats, and from their appropriate controls. [Ca²⁺]i was also determined in bone cells obtained fromin vivo insulin-treated NIDD rats. Obese (Wistar Kyoto) rats had increased body weight (313±13 vs. 249±4 g;P<0.01), decreased femur weights (0.68±0.05 vs. 0.89±0.05 g;P<0.05), similar glucose levels (148±5 vs. 139±3 mg/dl), and higher plasma insulin levels (6.0±0.5 vs. 0.7±0.1 ng/ml;P<0.01) when compared with their nonobese [(fa/+); (+/+)] littermates. Nonobese, NIDD rats, compared with their appropriate controls (nondiabetic Sprague Dawley rats) had higher plasma glucose levels (235±32 vs. 145±3 mg/dl;P<0.01) but their plasma insulins, body weights, and femur weights were similar to controls (0.7±0.1 vs 0.6±0.1 ng/ml; 302±4 vs. 318±14 g; 0.97±0.4 vs. 0.98±0.04 g, respectively). Long-term (4 weeks) daily insulin treatment (2 u/100 g) of the NIDD rats increased their plasma insulin (1.9 ng/ml;P<0.05) and body weight (369±13 g;P<0.05) but did not change their plasma glucose levels (225±5 mg/dl), or femur weights (0.98±0.4 g). [Ca²⁺]i in bone cells derived from the femurs of obese animals was higher than in cells derived from their nonobese littermates (156±22 vs. 71±13 nM;P<0.01). In bone cells from NIDD rats, [Ca²⁺]i was lower compared with controls (146±22 vs. 229±19 nM;P<0.001). Insulin treatment of the diabetic animals augmented the decrease in [Ca²⁺]i in their bone cells (68±11 nM;P<0.005 compared with nontreated rats). These data reveal that [Ca²⁺]i in cultured bone cells from obese nondiabetic and nonobese NIDD rats differs from that of their controls. Compared with their controls, the changes in [Ca²⁺]i in bone cells from the NIDD and obese animals were in opposite directions. Whether the underlying mechanisms for the changes in cell [Ca²⁺]i in nondiabetic obese and nonobese NIDD animals differ, and whether the changes in [Ca²⁺]i observed in the cultured cells reflect thein vivo condition in bone cells of these animals are questions that await further investigations.     

Type 2 Diabetes Mellitus and the Catabolic Response to Surgery

Background: The authors tested the hypothesis that the catabolic responses to colorectal surgery are amplified in the presence of type 2 diabetes mellitus.

Methods: Seven nondiabetic and seven diabetic patients underwent a 6-h stable isotope infusion study (3 h fasted, 3-h glucose infusion at 4 mg [middle dot] kg-1 [middle dot] min-1) on the second postoperative day. Leucine rate of appearance (Ra), leucine oxidation, nonoxidative leucine disposal, and glucose Ra were assessed by L-[1-13C]leucine and [6,6-2H2]glucose. Circulating concentrations of glucose, lactate, insulin, glucagon, and cortisol also were determined.

Results: Diabetic patients had a higher leucine oxidation than nondiabetic patients (P = 0.0003), whereas leucine Ra and nonoxidative leucine disposal were not different. Administration of glucose did not affect leucine kinetics regardless of whether patients were diabetic. In diabetic patients, glucose Ra was greater than in the nondiabetic group (P = 0.0032). Glucose infusion suppressed the endogenous glucose Ra to a lesser extent in diabetic than in nondiabetic patients (P = 0.0048). Plasma glucose concentrations were higher in diabetic than in nondiabetic patients (P = 0.0203), both in the postabsorptive and the fed state. Circulating concentrations of glucagon were higher (P = 0.0065) and concentrations of insulin were lower (P = 0.0146) in the presence of diabetes, resulting in a lower insulin/glucagon ratio (P = 0.0002). In diabetic patients, the insulin/glucagon ratio increased during glucose infusion to a lesser extent than in the nondiabetic group (P = 0.0014).     

Type 2 diabetes mellitus and the catabolic response to surgery

BACKGROUND: The authors tested the hypothesis that the catabolic responses to colorectal surgery are amplified in the presence of type 2 diabetes mellitus. METHODS: Seven nondiabetic and seven diabetic patients underwent a 6-h stable isotope infusion study (3 h fasted, 3-h glucose infusion at 4 mg . kg . min) on the second postoperative day. Leucine rate of appearance (Ra), leucine oxidation, nonoxidative leucine disposal, and glucose Ra were assessed by L-[1-C]leucine and [6,6-H2]glucose. Circulating concentrations of glucose, lactate, insulin, glucagon, and cortisol also were determined. RESULTS: Diabetic patients had a higher leucine oxidation than nondiabetic patients (P = 0.0003), whereas leucine Ra and nonoxidative leucine disposal were not different. Administration of glucose did not affect leucine kinetics regardless of whether patients were diabetic. In diabetic patients, glucose Ra was greater than in the nondiabetic group (P = 0.0032). Glucose infusion suppressed the endogenous glucose Ra to a lesser extent in diabetic than in nondiabetic patients (P = 0.0048). Plasma glucose concentrations were higher in diabetic than in nondiabetic patients (P = 0.0203), both in the postabsorptive and the fed state. Circulating concentrations of glucagon were higher (P = 0.0065) and concentrations of insulin were lower (P = 0.0146) in the presence of diabetes, resulting in a lower insulin/glucagon ratio (P = 0.0002). In diabetic patients, the insulin/glucagon ratio increased during glucose infusion to a lesser extent than in the nondiabetic group (P = 0.0014). CONCLUSION: Protein catabolism after colorectal surgery is increased in patients with type 2 diabetes mellitus as reflected by an increased oxidative protein loss.     

Improving Metabolic Control Reverses the Histomorphometric and Biomechanical Abnormalities of an Experimentally Induced Bone Defect in Spontaneously Diabetic Rats

Insulin-dependent type 1 diabetes mellitus (IDDM) has been shown to alter the properties of bone and to impair fracture-healing in both humans and animals. The objective of this study was to examine changes in the histomorphometric and mechanical parameters of bone and remodeling during bone-defect healing, depending on the diabetic metabolic state in spontaneously diabetic BB/O(ttawa)K(arlsburg) rats, a rat strain that represents a close homology to IDDM in humans.A standardized bone-defect model was chosen and based on blood-glucose values at the time of surgery (mg%), postoperative blood-glucose course (mg%), and postoperative insulin requirements (IU/kg). A total of 120 spontaneously diabetic BB/OK rats were divided into groups with a well-compensated (n = 60; 169 ± 102 mg%; 230 ± 126 mg%; and 2.2 ± 1.1 IU/kg) or poorly compensated (n = 60; 380 ± 159 mg%; 359 ± 89 mg%; and 5.4 ± 1.1 IU/kg) metabolic state. Sixty LEW.1A rats served as the normoglycemic controls (93 ± 19 mg%). Fifteen animals from each group were killed on postoperative days 7, 14, 24, and 42, and specimens were processed undecalcified for quantitative bone histomorphometry and for biomechanical testing.Our study showed in terms of bone histomorphometry, within the first 14 days, that severe mineralization disorders occurred exclusively in the rats with a poorly compensated diabetic metabolic state with a highly significant (P < 0.001) or significant (P < 0.01) decrease of all fluorochrome-based parameters of mineralization, apposition, formation and timing of mineralization, as well as significantly decreased values of biomechanical properties (P < 0.05) in comparison to the spontaneously diabetic rats with a well-compensated metabolic state and to the control rats.Bone-defect healing in spontaneously diabetic BB/OK rats is retarded exclusively in a poorly compensated diabetic metabolic state. This study suggests that strictly controlled insulin treatment resulting in a well-compensated diabetic metabolic state will ameliorate the impaired early and late parameters of IDDM bone-defect healing.     

Indomethacin-induced augmentation of insulin release

The effect of indomethacin, a potent prostaglandin synthetase inhibitor upon portal venous glucose, glucagon, and insulin, was examined in eight glucose-loaded, nondiabetic adult male mongrel dogs, by examining the response of each animal to a standard enteral glucose challenge with and without indomethacin pretreatment. Mean portal venous insulin rose after glucose loading with the rise after indomethacin pretreatment being significantly greater (P < 0.001) and more prolonged than that seen in the control group. Mean basal glucagon was increased with indomethacin pretreatment relative to controls (P < 0.01) and remained so throughout the measurement period. The glucose tolerance curves generated in control and indomethacin pretreatment groups were of normal contour and magnitude, and indistinguishable from one another. The effects seen are presumably the consequence of prostaglandin synthetase inhibition and imply that prostaglandins may play a suppressor role in modulating the insulin response to a glucose challenge.     

PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the ligand-activated nuclear receptor superfamily, and plays an important role in lipid metabolism and glucose homeostasis. The purpose of this study is to determine whether the activation of PPARalpha by fenofbrate would improve diabetes and its renal complications in type II diabetes mellitus. Male C57 BLKS db/db mice and db/m controls at 8 weeks of age were divided to receive either a regular diet chow (db/db, n=8; db/m, n=6) or a diet containing fenofibrate (db/db, n=8; db/m, n=7). Mice were followed for 8 weeks. Fenofibrate treatment dramatically reduced fasting blood glucose (P<0.001) and HbA1c levels (P<0.001), and was associated with decreased food intake (P<0.01) and slightly reduced body weight. Fenofibrate also ameliorated insulin resistance (P<0.001) and reduced plasma insulin levels (P<0.05) in db/db mice. Hypertrophy of pancreatic islets was decreased and insulin content markedly increased (P<0.05) in fenofibrate-treated diabetic animals. In addition, fenofibrate treatment significantly reduced urinary albumin excretion (P<0.001). This was accompanied by dramatically reduced glomerular hypertrophy and mesangial matrix expansion. Furthermore, the addition of fenofibrate to cultured mesangial cells, which possess functional active PPARalpha, decreased type I collagen production. Taken together, the PPARalpha agonist fenofibrate dramatically improves hyperglycemia, insulin resistance, albuminuria, and glomerular lesions in db/db mice. The activation of PPARalpha by fenofibrate in mesangial cells may partially contribute to its renal protection. Thus, fenofibrate may serve as a therapeutic agent for type II diabetes and diabetic nephropathy.     

Lipid effects of obesity operations

To achieve weight reduction, and specifically to lower blood lipids, we performed the first 40- to 4-cm end-to-end jejunoileal bypass in August 1970. Since 1975 we have also used gastric bypass, modified from Alden, for weight reduction. Lipids from 205 jejunoileal bypass and 106 gastric bypass patients have been sequentially analyzed from 1 to 3 years postoperation. After jejunoileal bypass cholesterol was lowered 33% by 6 weeks after surgery (P < 0.001). By 12 months, the cholesterol was lowered 42% from a preoperative value of 189 ± 35 (mean ± 1 SD in mg%) to 110 ± 27, n = 205 → 159, P < 0.001; this reduction was maintained through 36 months postbypass. At 12 months after bypass the other lipids showed similar lowering: total serum lipids, 37% (from 677 ± 181 to 425 ± 106, n = 189 → 158, P < 0.001); phospholipids, 34% (220 ± 47 to 146 ± 35, n = 162 → 137, P < 0.001); SF 0–12 lipoproteins, 30% (275 ± 70 to 194 ± 47, n = 162 → 118, P < 0.001); and SF 12–400 lipoproteins, 42% (from 188 ± 14 to 110 ± 63, n = 162 → 118, P < 0.001). The gastric bypass also resulted in lipid lowering during the first year after the bypass operation. The cholesterol values were lowered 14% (from 191 ± 30 to 165 ± 31 mg%, n = 106 → 51, P < 0.001); total serum lipids, 20% (675 ± 138 to 541 ± 115, n = 82 → 36, P < 0.001); triglycerides, 35% (176 ± 98 to 114 ± 63, n = 106 → 51, P < 0.001); phospholipids, 17% (225 ± 39 to 186 ± 43, n = 79 → 36, P < 0.001); SF 0–12 lipoproteins, 21% (310 ± 85 to 245 ± 80, n = 71 → 28, P < 0.001); and SF 12–400 lipoproteins, 48% (170 ± 89 to 88 ± 99, n = 70 → 28, P < 0.001). Thus, both jejunoileal and gastric bypass lower the blood lipids, however, the jejunoileal effect is generally greater; specifically, the cholesterol reduction after jejunoileal bypass is three times that engendered by gastric bypass.     

Glucose Excursions Between States of Glycemia With Progression to Type 1 Diabetes in the Diabetes Prevention Trial�CType 1 (DPT-1)

OBJECTIVE

We characterized fluctuations between states of glycemia in progressors to type 1 diabetes and studied whether those fluctuations are related to the early C-peptide response to oral glucose.

RESEARCH DESIGN AND METHODS

Oral glucose tolerance tests (OGTTs) from differing states of glycemia were compared within individuals for glucose and C-peptide. Dysglycemic OGTTs (DYSOGTTs) were compared with normal OGTTs (NLOGTT), while transient diabetic OGTTs (TDOGTTs) were compared with subsequent nondiabetic OGTTs and with OGTTs performed at diagnosis.

RESULTS

Of 135 progressors with four or more OGTTs, 30 (22%) went from NLOGTTs to DYSOGTTs at least twice. Area under the curve (AUC) glucose values from the second NLOGTT were higher (P < 0.001) than values from the first NLOGTT. Among 98 progressors whose DYSOGTTs and NLOGTTs were synchronized for the time before diagnosis, despite higher glucose levels (P < 0.01 at all time points) in the DYSOGTTs, 30- to 0-min C-peptide difference values changed little. Likewise, 30- to 0-min C-peptide difference values did not differ between TDOGTTs and subsequent (within 3 months) nondiabetic OGTTs in 55 progressors. In contrast, as glucose levels increased overall from the first to last OGTTs before diagnosis (P < 0.001 at every time point, n = 207), 30- to 0-min C-peptide difference values decreased (P < 0.001).

CONCLUSIONS

Glucose levels fluctuate widely as they gradually increase overall with progression to type 1 diabetes. As glucose levels increase, the early C-peptide response declines. In contrast, glucose fluctuations are not related to the early C-peptide response. This suggests that changes in insulin sensitivity underlie the glucose fluctuations.Glucose levels can fluctuate substantially during the progression to type 1 diabetes (1). In this report, we examine glucose variability and explore its basis by comparing the C-peptide response to oral glucose between states of glycemia. The findings provide additional insights into the metabolic progression to type 1 diabetes.