Glycaemic control in pancreatectomized dogs with a wearable artificial endocrine pancreas

Summary A needle-type glucose sensor has been developed using a platinum electrode covered with immobilized glucose oxidase. Experiments with albumin-saline solution in vitro showed that at 5.5 mmol/l glucose concentration the output current generated was 1.2±0.4 nA (mean ± SD). The current increased as a linear function of glucose concentration over the range (0–27.7 mmol/l). The response time to reach 90% of the final plateau value was 16.2±6.2 s. The signal-to-noise ratio of the sensor was 15.8±2.6 decibels. The temperature coefficient in output was 2.3±1.0%/°C. The current output was not affected significantly by changes in oxygen tension of the solution in the range 25–150 mmHg.In vivo, the output current of sensors inserted into the subcutaneous tissues of dogs was directly related to blood glucose concentrations after oral glucose or meals. Daily checking of the sensors maintained in subcutaneous tissues in five dogs showed that the sensitivity decreased gradually to 87.2±7.6% at 72 h, and dropped significantly to 57.4±7.0% of the initial output by 96 h.A wearable artificial endocrine pancreas (18.0 × 17.7 × 7.9 cm, 700 g) was developed, consisting of a needle-type glucose sensor, a microcomputer system and a pump driving mechanism. Three pancreatectomized dogs were fitted with the system by inserting the sensor into subcutaneous tissue. By renewing the sensor every fourth day, the device could maintain the daily glucose variations in diabetic dogs within the range 5–9.5 mmol/l for 7 days.     

Programming of an open-loop system for I.V. insulin infusion in insulin-dependent diabetes

Summary The blood glucose of 10 stable unstressed uncomplicated insulin-dependent diabetics (age: 39 ± 4 years; duration of diabetes: 11 ± 1 years) was controlled by a preprogrammed open-loop system of i.v. insulin infusion during two randomized consecutive days. Individual constant basal insulin rates were determined by adapting the rate of the pump to obtain normoglycemia during an overnight infusion. The post-prandial doses of insulin, given as square waves (12 U/h) or boluses (120 U/h), were calculated on one day (type I programme) from the fractional individual insulin requirements during a previous external artificial pancreas run, and on the other day (type II programme), from the formula: constant basal rate (U/h) × amount of carbohydrates (g) × 0.4 if for breakfast, on × 0.15 if for midday and evening meal. Blood glucose control, which was similar for the two methods, was identical to that provided by the artificial pancreas closed-loop system for correction of post-prandial glycemic excursions (mean peak values: 7.0 ± 0.4, 7.2 ± 0.1, 7.0 ± 0.1 mmol/l for type I, type II and closed-loop programmes). Basal blood glucose was significantly higher with the open-loop system (7.2 ± 1.1, 6.8 ± 0.8, 4.8 ± 0.3 mmol/l for type I, type II and closed-loop programmes) because of a drift of the values during the first half of the night. Boluses gave a slightly better post prandial control than square waves but produced a late hyperglycemic rebound. Daily insulin doses required by type I, type II and closed-loop programmes were respectively 75 ± 7, 64 ± 5 and 80 ± 7 U. Individual basal rate was uniform (1.1 ± 0.1 U/h). From these results it is concluded: (1) the quality of blood glucose control obtained from open-loop and closed-loop systems of insulin infusion is remarkably similar; (2) our formula is adequate for preprogramming insulin for the prandial periods, but careful individual determination of the basal rate by use of a closed-loop system is required.     

Metformin reduces post-prandial insulin needs in type I (insulin-dependent) diabetic patients: Assessment by the artificial pancreas

Summary It has been suggested that biguanides should be used in Type 1 (insulin-dependent) diabetic patients in order to diminish insulin requirements and reduce the chances of insulin reactions. The efficacy of these compounds in such patients has been controversial. We have studied the effect of metformin (850mg) given at 08.00 h in diminishing insulin needs after a 60g carbohydrate mixed meal taken at 12.00 h, using an artificial pancreas and a sequential analysis of the results. The morning test dose of metformin or placebo was preceded by 48 h treatment with metformin (850mg twice daily) or placebo. After the eighth patient a 26% saving of insulin need was demonstrated in the metformin-treated group (p<0.01). Metformin is thus effective in reducing post-prandial insulin needs in Type 1 diabetic patients, although its use in such circumstances requires consideration of several other issues.     

B-cell function and blood glucose control in insulin dependent diabetics within the first month of insulin treatment

Summary Seventeen insulin dependent diabetics were studied after two to four weeks of insulin treatment in a situation approximating to their normal daily life. Some endogenous insulin secretion, assessed by plasma C-peptide determinations, was present in all. Plasma C-peptide concentration was positively correlated with the blood glucose concentration and increased after breakfast, lunch and dinner (p<0.01); both peak values and relative increases were lower than those observed in normal subjects (p<0.01). The highest insulin secretory capacity was found in subjects with the least unstable blood glucose concentration (r=0.57, p <0.03), and these patients required the smallest insulin doses (r=0.54, P<0.04). These findings demonstrate the metabolic importance of a preserved B-cell function.     

Blood glucose control and insulin secretion improved with combined therapy in type 2 diabetic patients with secondary failure to oral hypoglycaemic agents

The influence of combined therapy using insulin and oral hypoglycaemic agents on blood glucose control and on insulin secretion in Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents was evaluated. Type 2 diabetic patients (n = 180) (98 normal-weight, 82 over-weight), at least 3 years from diagnosis, and having poor blood glucose control on oral hypoglycaemic agents for at least 3 months (fasting plasma glucose greater than 10.0 mmol l-1) despite intensive efforts at improvement, were included in the study. A single daily insulin injection (human ultralente), at a dose of 0.22 +/- 0.07 U kg-1 d-1 in normal-weight and 0.33 +/- 0.10 U kg-1 d-1 in over-weight patients, was added to the previous dietary and drug treatment for 6 months. A progressive and significant (2p less than 0.001) reduction of the mean daily blood glucose was observed during the first 3 months of combined therapy (from 13.2 +/- 3.2 to 8.1 +/- 2.1 mmol l-1 in normal-weight and from 13.4 +/- 3.1 to 8.8 +/- 2.3 mmol l-1 in over-weight patients), with no further significant changes thereafter. A significant increase (2p less than 0.001) in the mean daily C-peptide concentration (from 0.50 +/- 0.30 to 0.71 +/- 0.29 nmol l-1 in normal-weight and from 0.78 +/- 0.36 to 1.00 +/- 0.41 nmol l-1 in over-weight patients) took place during combined therapy. No changes of body weight (+ 1.5 +/- 1.2 kg in normal-weight and + 1.0 +/- 1.0 kg in over-weight patients) were observed.     

Metasomatotrophic diabetes and its induction: Basal insulin secretion and insulin release responses to glucose,glucagon, arginine and meals

Summary Growth hormone treatment produced somatotrophic diabetes, with hyperglycaemia, polyuria, glycosuria and elevation in serum non-esterified fatty acids (NEFA) in dogs. Early in this diabetes, fasting serum immunoreactive insulin (IRI) rose 20-fold, the insulin/glucose (I/G) ratio rose 10-fold and in response to glucose infusion, the rise in IRI was twice the normal. In the latter half of the continued growth hormone treatment, the intensity of the diabetes increased, serum IRI declined to the normal level and the I/G ratio became subnormal. Late in the treatment, following glucose infusion, there was no change in serum IRI, no fall in NEFA and further depression of glucose tolerance. In metasomatotrophic diabetes, in which hyperglycaemia, glycosuria and high NEFA level persisted, fasting serum IRI was normal during several months, then became subnormal and the I/G ratio was diminished further. Following glucose IV there was no change in serum IRI, no fall in NEFA and low glucose tolerance. The normally-occurring rises in serum IRI following arginine and glucagon IV and after the ingestion of a meal were absent. These permanently diabetic dogs were responsive to insulin IV. The insulin content of the pancreas was reduced to about 1.2% of the normal after 14 months of this diabetes. From the sequence of change it is concluded that growth hormone induced metasomatotrophic diabetes by causing excessive secretion of insulin under basal and stimulative conditions, leading to permanent loss of function of the beta cells of the pancreatic islets, to such an extent that basal insulin secretion was low and the ability to secrete extra insulin in response to stimuli was lost.     

2009年中国成人2型糖尿病患者口服降糖药联合胰岛素治疗后血糖达标状况调查

目的了解我国2型糖尿病（T2DM）治疗及达标现状,重点了解口服降糖药联合胰岛素治疗血糖达标状况。方法由中华医学会糖尿病学分会“糖化血红蛋白监测网”项目组于2009年7至9月在全国范围内选择具有代表性的75个城市的400家医院参加本横断面研究。正在接受口服降糖药联合／不联合胰岛素治疗的年龄≥18岁的2型糖尿病患者均可进入研究。采用问卷形式调查患者一般信息、糖尿病病程、糖尿病并发症及合并症、糖化血红蛋白（HbAlc）、空腹血糖、餐后血糖及治疗药物。所有数据均使用SAS9．13软件进行统计学处理。结果最终共纳入T2DM患者143123例,其中男73544例,女69579例,中位年龄59岁,中位病程6年。在应用口服降糖药联合胰岛素治疗的患者中,最多应用的是预混胰岛素（65．5％,34487／52649）,其次是基础胰岛素（24．3％,12794／52649）,8．5％（4492／52649）的患者应用基础＋餐时胰岛素。按照HbAlc〈6．5％计算达标率,总体人群达标率为20．2％（28985／143123）。单纯使用口服药治疗的患者HbAlc达标率（23．4％,21163／90474）高于总体人群,使用口服降糖药联合胰岛素的患者HbAlc达标率（14．9％,7822／52649）低于总体人群。不同胰岛素治疗方案组达标率接近[基础胰岛素组15．2％（1944／12794）,预混胰岛素组14．9％（5150／34487）,基础＋餐时胰岛素组14．6％（656／4492）]。随着糖尿病病程延长,各胰岛素治疗方案组达标率均呈降低趋势（均P〈0．05）,早启用胰岛素的患者较晚启用胰岛素的患者达标率更高（均P〈0．01）。T2DM患者血压及血脂达标率分别为：血压23．5％（33676／143123）,甘油三酯37．4％（53550／143123）,总胆固醇41．4％（59320／143123）,高密度脂蛋白胆固醇19．2％（27418／143123）,低密度脂蛋白胆固醇41．7％（59671／143123）。结论我国T2DM患者HbAlc总体达标率低,口服药联合胰岛素的患者达标率低于总体达标率。提示大部分患者仍需要得到更加积极有效的个体化治疗。     

Glucose variability in subjects with normal glucose tolerance: Relations with body composition,insulin secretion and sensitivity

Background and aimsTo estimate the determinants of glucose variability (GV) in young and middle-aged non-obese subjects with normal glucose tolerance (NGT) we assessed relations between GV parameters, body composition, insulin secretion and sensitivity indices.MethodsThirty individuals with normal body mass index (BMI) and twenty overweight subjects were included. 24-hour mean glucose, time in range, time above range (TAR), time below range (TBR), standard deviation (SD), coefficient of variation (CV), mean amplitude of glucose excursions (MAGE), continuous overlapping net glycemic action (CONGA), J-index, lability index (LI), mean absolute glucose (MAG), M-value, high blood glucose index (HBGI), low blood glucose index (LBGI) were derived from continuous glucose monitoring. Body composition was assessed by DEXA. Insulin secretion and sensitivity was estimated by HOMA-IR and HOMA-B scores.ResultsOverweight subjects demonstrated higher mean glucose, CONGA, J-index and lower TBR, M-value and LBGI values. Mean glucose correlated positively with total, trunk, gynoid and android fat mass, while M-value and LBGI demonstrated negative correlations with these parameters. In multiple stepwise regression analysis, android fat mass was a predictor of mean glucose, CONGA, J-index, SD and MAGE, gynoid fat mass predicted J-index only, and total fat mass was associated inversely with MAG. Fasting insulin was a predictor of TAR, SD, CV, MAGE, MAG, LI and HBGI. HOMA-B was associated with CONGA, M-value and LBGI.ConclusionIn non-obese subjects with NGT mean glucose and GV parameters are related to fat mass and fat distribution. These relations can be mediated through insulin secretion and sensitivity.     

Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes

Summary Plasma insulin responses and insulin resistance were determined in 75 subjects, defined as having a normal, borderline abnormal, or abnormal oral glucose tolerance test (OGTT). Although considerable heterogeneity of insulin response existed, most patients with abnormal OGTT's had insulin responses greater than normal; none had insulin responses less than normal. The degree of insulin resistance also varied, but most patients with abnormal OGTT's were also abnormally insulin resistant. A significant correlation (r=0.64, p ±0.001) existed between insulin response and the degree of insulin resistance. However, when both variables were taken into consideration, the entire population could be divided into two groups. One group was characterized by both normal insulin responsiveness and sensitivity, the other by increased insulin response, associated with greater insulin resistance. Most patients with abnormal OGTT's fell into the latter group, but some had glucose intolerance without either an exaggerated insulin response or insulin resistance. These results suggest that true heterogeneity exists in patients with abnormal OGTT's.This work was supported in part by grants from the National Institutes of Health, #HL 08506 from the National Heart and Lung Institute and #RR-70 from the General Clinical Research Centers Branch, and from the Research Services of the Veterans AdministrationDr. Reaven is a Medical Investigator, Veterans AdministrationDr. Olefsky is a Clinical Investigator, Veterans Administration     

Perceptions and expectations of adults with type 1 diabetes for the use of artificial pancreas systems with and without glucagon addition: Results of an online survey

Background and aimsThe first hybrid artificial pancreas (AP) systems with insulin only (mono-hormonal) have recently reached the market while next generations systems are under development including those with glucagon addition (bi-hormonal). Understanding the expectations and impressions of future potential users about AP systems is important for optimal use of this clinically effective emerging technology.Methods and resultsAn online survey about AP systems which consisted of 50 questions was addressed to people with type 1 diabetes in the province of Quebec, Canada. Surveys were completed by 123 respondents with type 1 diabetes (54% women, mean (SD) age 40.2 (14.4) y.o., diabetes duration 23.7 (14.1) years, 58% insulin pump users and 43% glucose sensor users). Of the respondents, 91% understood how AP systems work, 79% trusted them with correct insulin dosing, 73% were willing to replace their current treatment with AP and 80% expected improvement in quality of life. Anxiety about letting an algorithm control their glucose levels was expressed by 18% while the option of ignoring or modifying AP instructions was favoured by 88%. As for bi-hormonal AP systems, 83% of respondents thought they would be useful to further reduce hypoglycemic risks.ConclusionsOverall, respondents expressed positive views about AP systems use and high expectations for a better quality of life, glycemic control and hypoglycemia reduction. Data from this survey could be useful to health care professionals and developers of AP systems.     

24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas

Summary Based on the known action of xanthine derivatives on the insulin secretion, the effect of pentoxifylline on carbohydrate homeostasis of type I (IDDM) and type II (NIDDM) diabetics was investigated. Pentoxifylline is known to exert a favorable influence on hemorheological disturbances in such patients. Twenty-four hour blood glucose pattern and insulin requirements were evaluated in type I and type II diabetics by the use of the artificial pancreas before and after a 14-day treatment with pentoxifylline 400 mg p.o. (Trental 400^?) t.i.d. During the stabilization period before treatment with pentoxifylline, NIDDM patients required 10.1±3.8 U of insulin and the IDDM 35±13.7 U. After 2 weeks on pentoxifylline, NIDDM required only 6.3±2.8 U (p<0.05) and IDDM 28.5±9.7 U (n.s.). Average blood glucose during the 24h decreased by 15.8±3.5% in NIDDM and by 10.3±2.5% in IDDM. Moreover, a significant smoothing of glucose fluctuations during the 24h was noted in both groups. It is concluded that pentoxifylline administered concurrently to any antidiabetic type of treatment leads to better blood glucose control as well as to prevention or delay of vascular complications. This work was supported by grants from the Social Ministry, Athens, Greece; Department of Internal Medicine I, University of Ulm, FRG;Deutsche Forschungsgemeinschaft SFB87 Endokrinologie, Ulm, FRG; the Alexander Onassis Foundation, Vaduz, Liechtenstein. Dedicated to Prof. Dr. med. h.c. Ernst F. Pfeiffer on the occasion of his 65th birthday anniversary.     

胰岛素控制血糖减轻Ⅰ型糖尿病小鼠心肌缺血/再灌注损伤

目的:研究Ⅰ型糖尿病(DM)小鼠心肌缺血/再灌注(I/R)损伤的变化,以及胰岛素(ISL)治疗控制血糖对Ⅰ型DM小鼠心肌I/R损伤的影响.方法:72只健康雄性昆明小鼠以链脲佐菌素(STZ)腹腔注射制备Ⅰ型DM模型,建模后用ISL治疗控制血糖2周.实验分为假手术(sham)组、I/R组、DM+I/R组、DM+ISL+I/...     

Effects of feeding and fasting on the insulin secretory response to glucose and sulfonylureas in intact rats and isolated perfused rat pancreas

Summary In intact rats 16 h of fasting reduced the plasma insulin response to i.v. stimulation with either glucose, tolbutamide or glibenclamide by 50–80 %, without affecting the extractable insulin content of the pancreas. In subsequent studies with the isolated perfused rat pancreas two distinct patterns of insulin release could be discerned during the secondary phase. In thefed state, glucose 1.5 mg/ml induced a more or less constant elevation of the insulin secretion rate over 30 min (type I). At glucose concentrations of 2 and 3 mg/ml the release pattern was characterized by progressively increasing secretion rates (type II pattern). Infusion of tolbutamide (0.2 mg/ml) lowered the threshold for glucose stimulation and induced both patterns of secretion at lower glucose concentrations.Fasting for 24 h caused a 70–80 % inhibition of insulin secretion per 30 min at glucose levels of 1.5 and 2 mg/ml. Decreased glucose sensitivity was indicated by a shift to the right of the entire dose-response curve for glucose and by reduced inhibition (30 %) at a glucose level of 3 mg/ml. The effect of tolbutamide was also strongly diminished. The percent inhibition of the response to tolbutamide at different levels of glucose showed a pattern of inhibition similar to that observed with glucose alone. These findings suggest that the glucose-dependent release mechanism is highly sensitive to relatively short periods of fasting.Presented in part at the Sixth Annual Meeting of the European Association for the Study of Diabetes, Warsaw, September 1970.Supported by a grant from the Netherlands Organization for the Advancement of Pure Research (Z.W.O.).     

Exaggerated insulin secretion in Pima Indians and African-Americans but higher insulin resistance in Pima Indians compared to African-Americans and Caucasians.

AIMS: African-Americans have a higher prevalence of Type 2 diabetes than Caucasians, but a lower prevalence than Pima Indians. Studies suggest that both African-Americans and Pima Indians are more insulin resistant and have higher acute insulin secretory responses to glucose than Caucasians; however, a direct comparison between these three populations is lacking. METHODS: We measured insulin secretory responses to intravenous glucose (acute insulin response, AIR, 25 g ivGTT); insulin action at physiological (M-low) and supra-physiological (M-high) levels of hyperinsulinaemia (2-step hyperinsulinaemic clamp); basal and insulin-suppressed endogenous glucose production in 30 African-Americans, 30 Pima Indians and 30 Caucasians with normal glucose tolerance who were carefully matched for age, sex, and body fat (hydrodensitometry or DEXA). A subgroup of 24 subjects from each group additionally underwent a standardized mixed meal test. RESULTS: M-low was lower in Pima Indians (0.50 +/- 0.03) compared to Caucasians (0.59 +/- 0.02, P = 0.02) and African-Americans [0.58 +/- 0.03 mg/kgEMBS/min, log10 (means +/- SE), P = 0.03] but was not different between African-Americans and Caucasians. Basal endogenous glucose production was lower in Pima Indians (2.43 +/- 0.06) compared to African-Americans (2.70 +/- 0.06, P = 0.02) and was not different between Pima Indians and Caucasians (2.59 +/- 0.09 mg/kgEMBS/min) or African-Americans and Caucasians (all P > 0.18). Insulin-suppressed endogenous glucose production during the clamp was not different among the groups (all P > 0.40). AIR was higher in both African-Americans (13.51 +/- 0.26) and Pima Indians (13.72 +/- 0.27) compared to Caucasians (12.33 +/- 0.25 pM, log10, both P < 0.01). The areas under the curve for glucose in response to the oral glucose tolerance test and mixed meal test were higher in Pima Indians compared to African-Americans (P = 0.03 and P = 0.03, respectively) and Caucasians (P = 0.01, mixed meal test), but not different between African-Americans and Caucasians. CONCLUSIONS: Exaggerated glucose-stimulated insulin secretion, manifested initially as an increased response to an intravenous glucose challenge, appears to be a characteristic in people with normal glucose tolerance at higher risk for diabetes. Lower whole-body insulin sensitivity in Pima Indians compared to African-Americans, however, may contribute to the higher risk for Type 2 diabetes in Pima Indians compared to African-Americans.     

Plasma glucose and insulin responses to oral glucose in nonobese subjects and patients with endogenous hypertriglyceridemia

Plasma glucose and insulin responses to a 50-gm oral glucose challenge were determined in 396 nonobese subjects: 220 patients with endogenous hypertriglyceridemia and 176 normal persons. These groups were further subdivided on the basis of relative body weight: 1.0-1.1 and 1.1-1.2. Patients with endogenous hypertriglyceridemia whose obesity index was between 1.0 and 1.1 had significantly increased plasma glucose (more than 25%, P less than 0.001) and insulin (more than 18%, P less than 0.01) responses. Similar findings were also observed in patients with endogenous hypertriglyceridemia whose index of obesity was between 1.1 and 1.2, ie, there was a 25% increase in the plasma glucose response (P less than 0.001) and a 37% increase in the plasma insulin response (P less than 0.001). Thus, endogenous hypertriglyceridemia can occur in nonobese individuals, and these patients have an increase in their plasma glucose and insulin responses when weight-matched with nonobese normal subjects.     

Effect of a nutritional liquid supplement designed for the patient with diabetes mellitus (Glucerna SR) on the postprandial glucose state, insulin secretion and insulin sensitivity in healthy subjects

AIM: To identify the effect of a nutritional liquid supplement designed for the patient with diabetes mellitus (Glucerna SR) in single administration on the postprandial glucose state, insulin secretion and insulin sensitivity in healthy subjects. METHODS: A randomized, single-blind, cross-over, clinical trial was carried out in 14 young, healthy, non-obese, volunteers. A basal metabolic profile, which included glucose level, insulin, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinine, and uric acid, was measured. Subjects received a single administration of 300 kcal, gauged with water at 350 ml, of each of the following (at least 3 days apart): glucose 75 g, polymeric supplement (Ensure high calcium) 315 ml or Glucerna SR 323 ml. At the beginning of each administration and 30, 60, 90 and 120 min later, glucose and insulin concentrations were measured. Areas under the curve of glucose and insulin were calculated. First-phase and total insulin secretions and insulin sensitivity were also estimated. RESULTS: Glucose level at 120 min was significantly lower after receiving Ensure high calcium or Glucerna SR. Administration of Glucerna SR resulted in a significant reduction in the areas under the curve of glucose and insulin, as well as in total insulin secretion with a tendency to be lower in their first phase. Insulin sensitivity was increased. CONCLUSIONS: A single administration of Glucerna SR to healthy subjects decreased the postprandial glucose and insulin states, as well as the insulin secretion; insulin sensitivity increased.     

Effect of high sucrose diet on insulin secretion and insulin action. A study in rats with non-insulin-dependent diabetes induced by streptozotocin

Summary The effects of chronic high sucrose feeding for 1 month on in vivo and in vitro insulin secretion and on in vivo insulin action were studied in rats with non-insulin-dependent diabetes. As compared to the standard diet, the high sucrose diet induced an increase of the in vivo insulin response to an intravenous load and deteriorated the glucose tolerance as attested by significantly lower rates of glucose disppearance (K values, p<0.001). The increased insulin secretion in response to glucose in vivo seems to be related to a slight increase of the pancreatic B-cell reactivity to glucose, since it was still observed in vitro with the isolated perfused pancreas preparation. By contrast, B cells of sucrose-fed rats exhibited in vitro a significantly lowered (p<0.01) response to acetylcholine and arginine. The insulin action in the sucrose-fed diabetic rats was quantified in vivo with the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production and glucose utilisation were studied in anaesthetized rats while in the postabsorptive state. The basal glucose utilisation was found significantly higher (p<0.001) in sucrose-fed rats. During the clamp studies the glucose utilisation induced by submaximal (450 mU/l) insulin level was significantly less important (p<0.01) in the sucrose-fed rats than in the chow-fed rats. Following a maximal hyperinsulinaemia (5000 mU/l) the glucose utilisation was similar in both groups. This suggests that insulin-mediated glucose uptake is decreased over the range of submaximal plasma insulin levels in the sucrose-fed diabetic rats. In the basal state hepatic glucose production was significantly higher (p<0.001) in sucrose-fed rats. During the clamp studies, the suppression of glucose production induced by submaximal or maximal insulin levels was significantly less effective (p<0.01) in the sucrose-fed rats as compared to chow-fed rats, thus suggesting that the liver becomes resistant to insulin action after sucrose feeding. Finally, these results suggest that restriction of complex carbohydrates in favor of sucrose in insulin-deficient rats leads to metabolic events likely to develop insulin resistance in target tissues.     

Treatment with intravenous insulin followed by continuous subcutaneous insulin infusion improves glycaemic control in severely resistant Type 2 diabetic patients.

AIMS: Despite high-dose s.c. insulin therapy, some Type 2 diabetes mellitus (DM) patients remain in poor metabolic control. We investigated whether a period of euglycaemia using i.v. insulin, followed by continuous subcutaneous insulin infusion (CSII), would ameliorate the deleterious effects of hyperglycaemia on insulin sensitivity and result in sustained, improved metabolic control. METHODS: In a prospective observational study, eight Type 2 DM patients with severe insulin resistance (insulin dose 1.92 +/- 0.66 U/kg per day (mean +/-sd)), in poor metabolic control (HbA(1c) 12.0 +/- 1.7%), were treated with i.v. insulin for 31 +/- 10 days aimed at euglycaemia, followed by CSII therapy for 12 months, using insulin lispro. Before and after 28 +/- 6 days of i.v. insulin treatment, insulin sensitivity was measured by a hyperinsulinaemic euglycaemic clamp. RESULTS: Euglycaemia was reached after 12 +/- 6 days of i.v. insulin treatment. Subsequently, the i.v. insulin dose required to maintain euglycaemia decreased from 1.7 +/- 0.9 to 1.1 +/- 0.6 U/kg per day (P < 0.005). Whole body glucose uptake increased from 12.7 +/- 5.7 to 22.4 +/- 8.8 micromol/kg per min (P < 0.0005). HbA(1c) decreased to 8.9 +/- 1.2% after 28 +/- 6 days, to 7.1 +/- 0.6% after 6 months and to 8.3 +/- 1.4% after 12 months (P < 0.001 vs. pretreatment, for all). Lipid profile improved and plasminogen activator inhibitor type 1 levels decreased significantly. Mean body weight did not change. CONCLUSIONS: In Type 2 diabetic patients, who are poorly controlled despite high-dose s.c. insulin treatment, a period of 2 weeks of euglycaemia achieved by i.v. insulin reverses hyperglycaemia-induced insulin resistance and substantially improves metabolic control. Subsequent CSII treatment, using insulin analogues, appears to maintain improved metabolic control for at least 1 year. This approach is promising but needs further evaluation.     

Lack of influence of arginine preloading on the insulin response to I.V. glucagon in children and adolescents

Summary Nine normal children (6 males and 3 females) aged from 7 1/2 to 14 1/2 years underwent a 30-min arginine infusion (0.5 g/kg) followed at 90 min by one bolus i.v. glucagon injection (0.03 mg/kg). On a separate occasion the same children underwent an i.v. glucagononly test. No significant difference was found when the glucose and insulin responses in the two glucagon tests were compared, in contrast to previous findings that preloading with glucose resulted in a significantly increased response of insulin to glucagon. Established Investigator of the Chief Scientist’s Bureau Ministry of Health.     

Insulin binding to trophoblast plasma membranes and placental glycogen content in well-controlled gestational diabetic women treated with diet or insulin,in well-controlled overt diabetic patients and in healthy control subjects

Summary Insulin binding to trophoblast plasma membranes and the placental glycogen content were measured in twelve healthy women, in eleven well-controlled gestational diabetic women who were treated either with diet alone (n=4) or with insulin (n=7) and in 18 women with well-controlled overt diabetes mellitus (six White B; four White C; eight White D). The competitive binding assay was carried out with 22 concentrations of unlabelled insulin. Binding data were analysed by a non-linear direct model fitting procedure assuming one non-cooperative binding site. Maximum specific binding was unchanged in the total collective of gestational diabetic women, but was decreased by 30% in those treated with diet (6.2±2.2%) and increased by 90% in insulin-treated women (16.4±10.2%) as compared to the control subjects (8.7±2.5%). The diet-treated women had only 40% as many and those treated with insulin had more than twice as many receptors compared to control subjects on a per mg protein basis and if expressed per total placenta. In patients with overt diabetes mellitus maximum specific binding (18.5±10.6 %) was higher (p<0.05) due to more receptors compared to control subjects but was similar to the insulin-treated gestational diabetic patients. Maximum specific binding and receptor concentrations did not correlate linearly with maternal plasma insulin levels. Receptor affinities were virtually similar in all groups (1.8·10⁹ l/mol). The placental glycogen content was reduced (p<0.05) to about 80% of that of control subjects in the diet-treated collective, whereas it was unchanged compared to control subjects in the insulin-treated gestational diabetic women despite a 40% increase (p<0.001) of the maternal-to-cord serum glucose ratio. In overt diabetic patients the maternal-to-cord serum glucose ratio and the placental glycogen content were higher (p<0.05) than in the control subjects. We conclude that trophoblast plasma membranes from gestational diabetic women treated with diet alone express less and those from women treated with insulin express more insulin receptors than those from a healthy control group in vitro. These differences could not have been disclosed without consideration of the mode of treatment. Trophoblast plasma membranes from overt diabetic women have more insulin receptors than those from healthy control subjects.