Progress in practical endocrinology. The Glucosensor Unitec Ulm--a portable monitor for continuous blood glucose measurement

The Glucosensor Unitec Ulm is the first portable glucose sensor for continuous glucose monitoring in blood. The Glucosensor weighs 850 g and has a size of 15 x 19 x 7 cm. Over a 24 hr period 15-25 ml of blood are withdrawn for continuous measurement, depending on the pumping velocity. Its storing capacity for data of blood glucose readings amounts to 32 KB. With the Glucosensor "long-term glucograms" under near-normal conditions can be registered. The glucograms enable the physician to recognize the different deteriorations of glucose met- abolism eg. periods of silent hypoglycemia during the night as well as postprandial hyperglycemia. The degree of glycemic control of diabetic patients can be analyzed and the effect of blood glucose lowering therapeutics can be realistically assessed.     

Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent.

To study the effect of hydroxychloroquine (HCQ) on glucose and insulin homeostasis, healthy rats were dosed with 160 mg x kg (-1) x day(-1) of HCQ orally, and streptozocin-induced diabetic rats received 80, 120, and 160 mg x kg(-1) x day(-1) of HCQ, while controls received normal saline. Ten days after treatment with HCQ, healthy animals were challenged intravenously with insulin or glucose, while diabetic rats were given only an i.v. injection of insulin. In healthy rats, the areas within and under the glucose concentration - time curve following insulin and glucose challenge were estimated. In diabetic animals, the areas under the curve for both the percent change in serum glucose from baseline (AUG) and the percent change in serum insulin from baseline (AUI) were used as pharmacodynamic end points. In healthy rats, HCQ did not influence fasting serum glucose concentrations or glycemic profiles following i.v. administration of glucose or insulin. In diabetic rats, AUG and AUI were increased dependent on blood HCQ concentrations. The normal homeostatic mechanisms responsible for insulin-glucose regulation may compensate for possible HCQ-induced reduction of insulin metabolism in healthy rats. The HCQ dose- or concentration-effect relationships for glucose and insulin were linear over the range of HCQ concentrations tested. It is concluded that HCQ significantly elevated insulin blood concentration resulting in reduced glucose levels in a concentration-dependent fashion in diabetic rats. HCQ may have therapeutic potential in the treatment of type I and type II diabetes.     

Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice

Hypoglycemia-induced counterregulatory failure is a dangerous complication of insulin use in diabetes mellitus. Controlled hypoglycemia studies in gene knockout models, which require the use of mice, would aid in identifying causes of defective counterregulation. Because stress can influence counterregulatory hormones and glucose homeostasis, we developed glucose clamps with remote blood sampling in conscious, unrestrained mice. Male C57BL/6 mice implanted with indwelling carotid artery and jugular vein catheters were subjected to 2 h of hyperinsulinemic glucose clamps 24 h apart, with a 6-h fast before each clamp. On day 1, blood glucose was maintained (euglycemia, 178 +/- 4 mg/dl) or decreased to 62 +/- 1 mg/dl (hypoglycemia) by insulin (20 mU x kg(-1) x min(-1)) and variable glucose infusion. Donor blood was continuously infused to replace blood sample volume. Baseline plasma epinephrine (32 +/- 8 pg/ml), corticosterone (16.1 +/- 1.8 microg/dl), and glucagon (35 +/- 3 pg/ml) were unchanged during euglycemia but increased significantly during hypoglycemia, with a glycemic threshold of approximately 80 mg/dl. On day 2, all mice underwent a hypoglycemic clamp (blood glucose, 64 +/- 1 mg/dl). Compared with mice that were euglycemic on day 1, previously hypoglycemic mice had significantly higher glucose requirements and significantly lower plasma glucagon and corticosterone (n = 6/group) on day 2. Epinephrine tended to decrease, although not significantly, in repeatedly hypoglycemic mice. Pre- and post-clamp insulin levels were similar between groups. We conclude that counterregulatory responses to acute and repeated hypoglycemia in unrestrained, chronically cannulated mice reproduce aspects of counterregulation in humans, and that repeated hypoglycemia in mice is a useful model of counterregulatory failure.     

High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance

Endothelial dysfunction is a hallmark of Type 2 diabetes related to hyperglycemia and oxidative stress. Nitric oxide-dependent vasodilator actions of insulin may augment glucose disposal. Thus endothelial dysfunction may worsen insulin resistance. Intra-arterial administration of vitamin C improves endothelial dysfunction in diabetes. In the present study, we investigated effects of high-dose oral vitamin C to alter endothelial dysfunction and insulin resistance in Type 2 diabetes. Plasma vitamin C levels in 109 diabetic subjects were lower than healthy (36 +/- 2 microM) levels. Thirty-two diabetic subjects with low plasma vitamin C (<40 microM) were subsequently enrolled in a randomized, double-blind, placebo-controlled study of vitamin C (800 mg/day for 4 wk). Insulin sensitivity (determined by glucose clamp) and forearm blood flow in response to ACh, sodium nitroprusside (SNP), or insulin (determined by plethysmography) were assessed before and after 4 wk of treatment. In the placebo group (n = 17 subjects), plasma vitamin C (22 +/- 3 microM), fasting glucose (159 +/- 12 mg/dl), insulin (19 +/- 7 microU/ml), and SI(Clamp) [2.06 +/- 0.29 x 10(-4) dl x kg(-1) x min(-1)/(microU/ml)] did not change significantly after placebo treatment. In the vitamin C group (n = 15 subjects), basal plasma vitamin C (23 +/- 2 microM) increased to 48 +/- 6 microM (P < 0.01) after treatment, but this was significantly less than that expected for healthy subjects (>80 microM). No significant changes in fasting glucose (156 +/- 11 mg/dl), insulin (14 +/- 2 microU/ml), SI(Clamp) [2.71 +/- 0.46 x 10(-4) dl x kg(-1) x min(-1)/(microU/ml)], or forearm blood flow in response to ACh, SNP, or insulin were observed after vitamin C treatment. We conclude that high-dose oral vitamin C therapy, resulting in incomplete replenishment of vitamin C levels, is ineffective at improving endothelial dysfunction and insulin resistance in Type 2 diabetes.     

Gliclazide mainly affects insulin secretion in second phase of type 2 diabetes mellitus.

We studied the effect of the acute administration of gliclazide at 160 mg on insulin release during hyperglycaemic clamps in 12 type 2 diabetes patients, age 50 +/- 9.0 years, diabetes duration 5.5 +/- 4.8 years, fasting blood glucose 9.6 +/- 2.1 mmol/L (means +/- SD). After a 210 min of hyperinsulinaemic euglycaemic clamp (blood glucose 4.6 +/- 0.14mmol/L), gliclazide or placebo (randomised, double-blind, cross-over) was administered; 60 minutes later, a hyperglycaemic clamp (4hr) at 8mmol/L was started. Plasma C-peptide levels increased significantly after the administration of gliclazide (increment 0.17 +/- 0.15 vs. 0.04 +/- 0.07 nmol/L, p = 0.024) before the clamp. After the start of the hyperglycaemic clamp, the areas under the curve (AUC) for insulin and C-peptide did not differ from 0-10 min (first phase) with gliclazide. However, second-phase insulin release (30-240 min) was markedly enhanced by gliclazide. AUC plasma insulin (30 to 240 min) was statistically significantly higher after gliclazide (12.3 +/- 13.9 vs. -0.56 +/- 9.4 nmol/L x 210 min, p = 0.022); similarly, AUC plasma C-peptide (30 to 240 min) was also higher: 128 +/- 62 vs. 63 +/- 50 nmol/L x 210 min, p = 0.002). In conclusion, in long-standing type 2 diabetes the acute administration of gliclazide significantly enhances second phase insulin release at a moderately elevated blood glucose level. In contrast to previous findings in mildly diabetic subjects, these 12 type 2 diabetes patients who had an inconsiderable first phase insulin release on the placebo day, only showed an insignificant increase in first phase with gliclazide.     

Seven days of aerobic exercise training improves conduit artery blood flow following glucose ingestion in patients with type 2 diabetes

The vasodilatory effects of insulin account for up to 40% of insulin-mediated glucose disposal; however, insulin-stimulated vasodilation is impaired in individuals with type 2 diabetes, limiting perfusion and delivery of glucose and insulin to target tissues. To determine whether exercise training improves conduit artery blood flow following glucose ingestion, a stimulus for increasing circulating insulin, we assessed femoral blood flow (FBF; Doppler ultrasound) during an oral glucose tolerance test (OGTT; 75 g glucose) in 11 overweight or obese (body mass index, 34 ± 1 kg/m2), sedentary (peak oxygen consumption, 23 ± 1 ml·kg?1·min?1) individuals (53 ± 2 yr) with non-insulin-dependent type 2 diabetes (HbA1c, 6.63 ± 0.18%) before and after 7 days of supervised treadmill and cycling exercise (60 min/day, 60-75% heart rate reserve). Fasting glucose, insulin, and FBF were not significantly different after 7 days of exercise, nor were glucose or insulin responses to the OGTT. However, estimates of whole body insulin sensitivity (Matsuda insulin sensitivity index) increased (P < 0.05). Before exercise training, FBF did not change significantly during the OGTT (1 ± 7, -7 ± 5, 0 ± 6, and 0 ± 5% of fasting FBF at 75, 90, 105, and 120 min, respectively). In contrast, after exercise training, FBF increased by 33 ± 9, 39 ± 14, 34 ± 7, and 48 ± 18% above fasting levels at 75, 90, 105, and 120 min, respectively (P < 0.05 vs. corresponding preexercise time points). Additionally, postprandial glucose responses to a standardized breakfast meal consumed under "free-living" conditions decreased during the final 3 days of exercise (P < 0.05). In conclusion, 7 days of aerobic exercise training improves conduit artery blood flow during an OGTT in individuals with type 2 diabetes.     

Glycemic Control Promotes Pancreatic Beta-Cell Regeneration in Streptozotocin-Induced Diabetic Mice

Background

Pancreatic beta-cells proliferate following administration of the beta-cell toxin streptozotocin. Defining the conditions that promote beta-cell proliferation could benefit patients with diabetes. We have investigated the effect of insulin treatment on pancreatic beta-cell regeneration in streptozotocin-induced diabetic mice, and, in addition, report on a new approach to quantify beta-cell regeneration in vivo.

Methodology/Principal Findings

Streptozotocin-induced diabetic were treated with either syngeneic islets transplanted under the kidney capsule or subcutaneous insulin implants. After either 60 or 120 days of insulin treatment, the islet transplant or insulin implant were removed and blood glucose levels monitored for 30 days. The results showed that both islet transplants and insulin implants restored normoglycemia in the 60 and 120 day treated animals. However, only the 120-day islet and insulin implant groups maintained euglycemia (<200 mg/dl) following discontinuation of insulin treatment. The beta-cell was significantly increased in all the 120 day insulin-treated groups (insulin implant, 0.69±0.23 mg; and islet transplant, 0.91±0.23 mg) compared non-diabetic control mice (1.54±0.25 mg). We also show that we can use bioluminescent imaging to monitor beta-cell regeneration in living MIP-luc transgenic mice.

Conclusions/Significance

The results show that insulin treatment can promote beta-cell regeneration. Moreover, the extent of restoration of beta-cell function and mass depend on the length of treatment period and overall level of glycemic control with better control being associated with improved recovery. Finally, real-time bioluminescent imaging can be used to monitor beta-cell recovery in living MIP-luc transgenic mice.     

Chronic sodium-retaining action of insulin in diabetic dogs

Insulin-mediated sodium retention is implicated as a mechanism for hypertension in metabolic syndrome and type II diabetes. However, there is no direct experimental evidence for a sustained antinatriuretic effect of insulin outside of rodents, and all previous studies in dogs have been negative. This study used a novel approach to test for a chronic sodium-retaining action of insulin in dogs, by testing the hypothesis that natriuresis in type I diabetes is dependent on the decrease in insulin, rather than being due solely to osmotic actions of hyperglycemia. Dogs were chronically instrumented and housed in metabolic cages. Fasting blood glucose in alloxan-treated dogs was maintained at ~65 mg/dl by continuous intravenous insulin infusion. Then, a 6-day diabetic period was induced by either 1) decreasing the insulin infusion to induce type I diabetes (D; blood glucose = 449 ± 40 mg/dl) or 2) clamping the insulin infusion and infusing glucose continuously (DG; blood glucose = 470 ± 56 mg/dl). Control urinary sodium excretion (UnaV) averaged 70 ± 5 (D) and 69 ± 5 (DG) meq/day and increased on day 1 in both groups. UnaV remained elevated in the D group (115 ± 15 meq/day days 2-6), but it returned to control in the DG group (69 ± 11 meq/day days 2-6) and was accompanied by decreased lithium clearance. Thus, insulin had a sustained antinatriuretic action that was triggered by increased glucose, and it was powerful enough to completely block the natriuresis caused by hyperglycemia. These data may reveal an unrecognized physiologic function of insulin as a protector against hyperglycemia-induced salt wasting in diabetes.     

The artificial beta cell (Biostator) in the adjustment of instable diabetics--results after 20 months.

In 55 poorly controlled insulin-dependent diabetics, we tried to discover criteria for an improvement of metabolism by means of the "artificial beta-cell" (Biostator). To this end, during the first 24 h of hospitalization, blood glucose was monitored continuously under conventional insulin therapy (monitoring period). Insulin requirement was determined during the next 24 h by the artificial beta-cell (feedback period). Corrections of diabetes regimen were made with reference to the insulin consumption during the feedback period and to the extent of the postprandial blood sugar increases and decreases during the monitoring period. The resulting new diabetes regimen led to a significant improvement of the daily blood sugar profiles.     

Discovery of novel glucose-regulated proteins in isolated human pancreatic islets using LC-MS/MS-based proteomics

The prevalence of diabetes mellitus is increasing dramatically throughout the world, and the disease has become a major public health issue. The most common form of the disease, type 2 diabetes, is characterized by insulin resistance and insufficient insulin production from the pancreatic beta-cell. Since glucose is the most potent regulator of beta-cell function under physiological conditions, identification of the insulin secretory defect underlying type 2 diabetes requires a better understanding of glucose regulation of human beta-cell function. To this aim, a bottom-up LC-MS/MS-based proteomics approach was used to profile pooled islets from multiple donors under basal (5 mM) or high (15 mM) glucose conditions. Our analysis discovered 256 differentially abundant proteins (～p < 0.05) after 24 h of high glucose exposure from more than 4500 identified in total. Several novel glucose-regulated proteins were elevated under high glucose conditions, including regulators of mRNA splicing (pleiotropic regulator 1), processing (retinoblastoma binding protein 6), and function (nuclear RNA export factor 1), in addition to neuron navigator 1 and plasminogen activator inhibitor 1. Proteins whose abundances markedly decreased during incubation at 15 mM glucose included Bax inhibitor 1 and synaptotagmin-17. Up-regulation of dicer 1 and SLC27A2 and down-regulation of phospholipase Cβ4 were confirmed by Western blots. Many proteins found to be differentially abundant after high glucose stimulation are annotated as uncharacterized or hypothetical. These findings expand our knowledge of glucose regulation of the human islet proteome and suggest many hitherto unknown responses to glucose that require additional studies to explore novel functional roles.     

Inpatient Management of Diabets Mellitus Among Noncritically Ill Patients at the University Hospital of Puerto Rico

ObjectiveTo describe the state of glycemic control in noncritically ill diabetic patients admitted to the Puerto Rico University Hospital and adherence to current standard of care guidelines for the treatment of diabetes.MethodsThis was a retrospective study of patients admitted to a general medicine ward with diabetes mellitus as a secondary diagnosis. Clinical data for the first 5 days and the last 24 hours of hospitalization were analyzed.ResultsA total of 147 noncritically ill diabetic patients were evaluated. The rates of hyperglycemia (blood glucose ≥ 180 mg/dL) and hypoglycemia (blood glucose < 70 mg/dL) were 56.7 and 2.8%, respectively. Nearly 60% of patients were hyperglycemic during the first 24 hours of hospitalization (mean random blood glucose, 226.5 mg/dL), and 54.2% were hyperglycemic during the last 24 hours of hospitalization (mean random blood glucose, 196.51 mg/dL). The mean random last glucose value before discharge was 189.6 mg/dL. Most patients were treated with subcutaneous insulin, with basal insulin alone (60%) used as the most common regimen. The proportion of patients classified as uncontrolled receiving basal-bolus therapy increased from 54.3% on day 1 to 60% on day 5, with 40% continuing to receive only basal insulin. Most of the uncontrolled patients had their insulin dose increased (70.1%); however, a substantial proportion had no change (23.7%) or even a decrease (6.2%) in their insulin dose.ConclusionThe management of hospitalized diabetic patients is suboptimal, probably due to clinical inertia, manifested by absence of appropriate modification of insulin regimen and intensification of dose in uncontrolled diabetic patients. A comprehensive educational diabetes management program, along with standardized insulin orders, should be implemented to improve the care of these patients. (Endocr Pract. 2014;20:452-460)     

Synthetic 1-24 ACTH-stimulated insulin release in bilaterally adrenalectomized patients

The plasma insulin and blood glucose responses to synthetic 1-24 ACTH were studied in 21 patients bilaterally adrenalectomized for pituitary-dependent Cushing's syndrome and in 8 healthy adults. In the adrenalectomized patients, intravenous 1-24 ACTH administration was followed by an increase in plasma insulin concentrations after 15 and 30 min and a fall in blood glucose after 30 min. In healthy subjects no significant changes in plasma insulin and blood glucose levels were found. The presence of intact adrenals seems to be the cause of the different responses of insulin to 1-24 ACTH injection in these two groups.     

Impaired fatty acid oxidation in muscle of aging rats perfused under basal conditions

The purpose of the present study was to examine the utilization of fatty acids (FA) and muscle substrates by skeletal muscle in young, middle-aged, and old adult rats under conditions of euglycemia with low insulin levels. Male Fischer 344 x Brown Norway rats aged 5, 15, or 24 mo underwent hindlimb perfusion with a medium of 8 mM glucose, 1 mM palmitate, 25 microU/ml insulin, [1-(14)C]palmitate, and [3-(3)H]glucose. Glucose and palmitate uptake were similar among age groups. The percent and total palmitate oxidized (nmol.min(-1).g(-1)) were 30-36 and 41-49% lower (P < 0.05) in 15-mo- and 24-mo-old than in 5-mo-old animals. Compared with 5-mo- and 15-mo-old animals, pre- and postperfusion muscle triglyceride (TG) levels were significantly (P < 0.05) elevated 91-305% in red and 118-219% in white muscles of 24-mo-old animals. Fatty acid-binding protein content was 40-64% higher (P < 0.05) in 24-mo- than in 5-mo- or 15-mo-old animals. In red muscle, hormone-sensitive lipase (HSL) content was 28% lower (P < 0.05) in 24-mo- than in 5-mo-old animals. These results indicate that, under euglycemic conditions in the presence of low insulin levels, the reduction in FA disposal to oxidation and the decrease in HSL content may contribute to the accumulation of TG in muscle of old animals.     

Assessment of type II diabetes mellitus using irregularly sampled measurements with missing data

Diabetes mellitus is one of the leading diseases in the developed world. In order to better regulate blood glucose in a diabetic patient, improved modelling of insulin-glucose dynamics is a key factor in the treatment of diabetes mellitus. In the current work, the insulin-glucose dynamics in type II diabetes mellitus can be modelled by using a stochastic nonlinear state-space model. Estimating the parameters of such a model is difficult as only a few blood glucose and insulin measurements per day are available in a non-clinical setting. Therefore, developing a predictive model of the blood glucose of a person with type II diabetes mellitus is important when the glucose and insulin concentrations are only available at irregular intervals. To overcome these difficulties, we resort to online sequential Monte Carlo (SMC) estimation of states and parameters of the state-space model for type II diabetic patients under various levels of randomly missing clinical data. Our results show that this method is efficient in monitoring and estimating the dynamics of the peripheral glucose, insulin and incretins concentration when 10, 25 and 50 % of the simulated clinical data were randomly removed.     

一次性静脉注射高剂量链脲佐菌素建立1型糖尿病小型猪模型

目的：探讨通过一次性注射高剂量链脲佐菌素（ streptozotocin,STZ）方法建立1型糖尿病小型猪模型的可行性。方法中华实验小型猪耳缘静脉一次性注射链脲佐菌素溶液150 mg/kg,分别在给药前和给药后10 min、30 min、90 min、第1天、第2天、第3天和第7天空腹采集静脉血,动态监测空腹血糖,并利用静脉糖耐量实验和C肽释放实验对模型进行鉴定。结果给药后第1天开始,模型组空腹血糖明显升高并始终维持在16.7～20.6 mmol/L的浓度范围,达到糖尿病标准;静脉葡萄糖耐量试验和C肽释放实验结果表明,静脉注射体积分数50％的葡萄糖1 h后模型猪血糖浓度高于11.1 mmol/L,2 h后未能恢复至空腹血糖水平;而胰岛素和C肽在注入葡萄糖后基本未发生任何反应,始终保持痕量水平。结论一次性静脉注射大剂量链脲佐菌素的方法能够成功建立1型糖尿病小型猪模型。     

Brittle diabetes: long-term control with a portable,continuous, intravenous insulin infusion system.

A young woman had severe brittle diabetes mellitus that was critically unmanageable with all conventional insulin treatment. Continuous subcutaneous and intramuscular infusions of insulin also failed to control her metabolic instability. Use of a continuous intravenous infusion, however, whereby a portable, variable-rate, battery-operated syringe pump delivered insulin through a subcutaneously tunnelled central venous catheter, resulted in good control. When she was receiving hourly intramuscular insulin injections (a mean of 778 IU daily) mean blood glucose concentrations had been 22.1 +/- 1.4 mmol/l (398 +/- 25 mg/100 microliters). After she had received the intravenous infusion for one month as an outpatient mean blood glucose concentration was 8.2 +/- 0.46 mmol/l (148 +/- 8 mg/100 microliters) and only 80 IU insulin daily was required. Follow-up after over five months of use showed that few complications had occurred. The system is simple to use and safe, and the diabetes had been stabilised such that she could enjoy a near-normal life style.     

A Continuous Glucose Monitoring System (CGMS) - a promising approach for improving metabolic control in persons with type 1 Diabetes mellitus treated by insulin pumps

This pilot study deals with the possibilities of a Continuous Glucose Monitoring System (CGMS, Minimed- Medtronic) to optimize insulin substitution. Ten persons with type 1 diabetes mellitus treated by means of an insulin pump entered the study and eight of them completed the protocol. CGMS was introduced for a period of 5 days. The standard dinner (60 g of carbohydrates) and overnight fasting were designed to ensure standard night conditions in all persons in the study while maintaining their usual daily eating routine, physical exercise and assessment of prandial insulin boluses. The only adaptation of basal rates of insulin pump was performed on day 3. Comparison of the mean plasma glucose concentration (0:00-24:00 hrs) between day 2 (before adaptation) and day 4 (following adaptation) was made. An independent comparison of the mean plasma glucose concentration between the night from day 2 till day 3 (22:00-6:00 hrs) and the night from day 4 till day 5 (22:00-6:00 hrs) was performed. The mean plasma glucose investigated by means of CGMS improved in the 24-hour period in 5 out of 8 persons and in the night fasting period (22:00 to 6 hrs) in 6 out of 8 persons. The CGMS is a useful means for assessment of the effectiveness of basal rate and prandial insulin doses in persons with type 1 diabetes treated by means of an insulin pump. However, further studies are necessary to improve the algorithm for insulin substitution.     

Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study

The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5–10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1±7.9% pretreatment vs. 45.4±4.9% during ORMD-0801 treatment; p = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00867594","term_id":"NCT00867594"}}NCT00867594.     

Association of obesity,diabetes, serum lipids and blood pressure regulates insulin action

Insulin resistance is present in patients with Type 2 diabetes mellitus as well as in obese patients without diabetes. The aim of our study was to compare insulin action in diabetic and control persons with or without obesity and to evaluate the influence of serum cholesterol, serum triglyceride and blood pressure on metabolic variables of insulin action. We examined 42 Type 2 diabetic patients and 41 control persons with body mass index (BMI) from 21.1 to 64.5 kg x m(-2), and 33 to 71 years old. The isoglycemic hyperinsulinemic clamp technique was performed at an insulin infusion rate of 1 mU x kg(-1) x min(-1) during 120 min. We evaluated the metabolic clearance rate of glucose (MCR(G), ml x kg(-1) x min(-1)) as the most important indicator of insulin action by isoglycemic clamp. The Pearson's correlation and multiple regression models were used to compare studied factors with the insulin action. We found following predictors of insulin resistance expressed in the relationship with MCR(G): BMI (r = -0.68, p<0.001), plasma glucose concentration (r = -0.66, p<0.001), cholesterol (r=-0.55, p<0.001), triglycerides (r = -0.54, p<0.001) and mean blood pressure (r = -0.38, p<0.01). From the multiple regression analysis we conclude that obesity may have even greater influence on the insulin action than diabetes mellitus itself.     

Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice

Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for 10 days. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Hepatic glucose production (HGP) and metabolic clearance rate (MCR) of glucose were determined with stable isotope techniques. Blood glucose and hepatic and whole body insulin sensitivity remained unaffected upon treatment in lean mice, despite increased hepatic triglyceride contents (61.7 +/- 7.2 vs. 12.1 +/- 2.0 nmol/mg liver, P < 0.05). In ob/ob mice, LXR activation resulted in lower blood glucose levels and significantly improved whole body insulin sensitivity. GW-3965 treatment did not affect HGP under normo- and hyperinsulinemic conditions, despite increased hepatic triglyceride contents (221 +/- 13 vs. 176 +/- 19 nmol/mg liver, P < 0.05). Clamped MCR increased upon GW-3965 treatment (18.2 +/- 1.0 vs. 14.3 +/- 1.4 ml x kg(-1) x min(-1), P = 0.05). LXR activation increased white adipose tissue mRNA levels of Glut4, Acc1 and Fasin ob/ob mice only. In conclusion, LXR-induced blood glucose lowering in ob/ob mice was attributable to increased peripheral glucose uptake and metabolism, physiologically reflected in a slightly improved insulin sensitivity. Remarkably, steatosis associated with LXR activation did not affect hepatic insulin sensitivity.