Measurement of an index of muscle capillary permeability and its correlation with serum insulin values in maturity-onset diabetic subjects.

1. An index of capillary permeability was obtained by measuring the ratio of the clearance rate of 77Br to that of 133Xe in the anterior tibial muscle, after a short period of maximal ischaemic exercise. 2. Seventeen control subjects and thirty-two maturity-onset, non-insulin-treated diabetic subjects, aged 60 years or less, were studied. Short glucose tolerance tests were performed in the diabetic subjects during which blood sugar and serum insulin concentrations were estimated. 3. The 77Br/133Xe clearance ratio was increased in the diabetic subjects compared with the control subjects. In the diabetic subjects, there was an inverse correlation between the insulin at 60 min after glucose and the 77Br/133Xe clearance ratio. There was also a direct correlation between the 77Br/133Xe clearance ratio and the age of the patient in the diabetic group but not in the control group. 4. The results demonstrate that a reduced insulin response to oral glucose is associated with increased capillary permability and may play a role in the development of microangiopathy.     

Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin-resistant humans.

Insulin-stimulated glycogen synthase activity in human muscle correlates with insulin-mediated glucose disposal and is reduced in insulin-resistant subjects. Inhibition of the cyclic AMP-dependent protein kinase (A-kinase) is considered as a possible mechanism of insulin action for glycogen synthase activation. In this study, we investigated the time course of insulin action on human muscle A-kinase activity during a 2-h insulin infusion in 13 insulin-sensitive (group S) and 7 insulin-resistant subjects (group R). Muscle biopsies were obtained from quadriceps femoris muscle at times 0, 10, 20, 40, and 120 min. Insulin infusion resulted in significant inhibition of A-kinase activity at 20 and/or 40 min using 0.2, 0.6, and 1.0 microM cyclic AMP in group S. A-kinase activities both before and after insulin administration were lower in group S than in group R using 0.6 microM cyclic AMP. The decrease in apparent affinity for cyclic AMP during insulin infusion was larger for group S compared with group R. Glycogen synthase activity increased significantly after insulin infusion in both groups and was higher in group S compared with group R. The data suggest that a defective response of A-kinase to insulin in insulin-resistant subjects could contribute to their reduced insulin stimulation of skeletal muscle glycogen synthase.     

Muscle fiber composition and capillary density in Turner syndrome: evidence of increased muscle fiber size related to insulin resistance

OBJECTIVE: To assess muscle fiber composition and capillary density in Turner syndrome, a condition linked with insulin resistance and increased frequency of type 2 diabetes, and link these findings with insulin sensitivity and physical fitness. RESEARCH DESIGN AND METHODS: A total of 10 patients with Turner syndrome who were off hormone replacement therapy (aged 32.7 +/- 8.9 years) and a control group of 14 normal women (aged 35.6 +/- 9.3 years) were studied. None of the participants had diabetes or any family history of type 2 diabetes. An oral glucose tolerance test was performed, and insulin sensitivity was assessed by homeostasis model assessment (HOMA) and a composite whole-body insulin sensitivity index (ISI(comp)). Physical fitness was assessed, and a muscle biopsy was obtained. RESULTS: Women with Turner syndrome were insulin resistant, as seen by a lower ISI(comp) (P = 0.003) and increased glucose (P < 0.0005) and insulin (P = 0.01) levels at 120 min. Impaired glucose tolerance was present in most Turner syndrome patients (6 of 10), but not in the control subjects. Women with Turner syndrome had an increased size of type IIa fibers (P = 0.01), whereas the size of their type I and IIa fibers were comparable with the control group. The groups did not differ in percentage of type I, Iia, or IIx fibers, and there was no difference in the capillary density. Significant correlations were found among ISI(comp), the HOMA index (R(HOMA)), and the mean area of type IIa fibers (ISI(comp): r = -0.632, P = 0.002; R(HOMA): r = 0.570, P = 0.006). Furthermore, capillaries/type IIa fibers correlated significantly with ISI(comp) (r = -0.618, P = 0.01). There were no significant correlations between VO(2max) and muscle fiber composition. CONCLUSIONS: Healthy women with Turner syndrome are characterized by impaired glucose tolerance, insulin resistance, low physical capacity, and enlarged type IIa muscle fibers, indicating diminished oxygen and substrate supply for metabolic processes. These findings could be indicative of a prediabetic state.     

Insulin and growth hormone secretion stimulated by intravenous administration of arginine in the low insulin responders (prediabetes?)

Twelve apparently healthy subjects who showed a low insulin response to glucose were selected from two different age groups, 6 from youngers aged 19 to 22 and 6 from olders above 65 years old, and responses of insulin and growth hormone secretion to an intravenous administration of arginine were investigated. Incidence of low insulin responders, who showed the peak value of plasma insulin during GTT below 45 muU/ml, was 9% among the young subjects and 24% among the old ones. Insulin secretion stimulated by arginine in 6 young low responders was not different from that in the control group matched with regard to age and body weight, and the values of growth hormone during arginine infusion were higher than those of the control group. In the old low insulin responders, insulin secretion stimulated by arginine was significantly lower than that in the control group, but the growth hormone secretion was not different from that in control. The present study showed that insulin and growth hormone secretion stimulated by arginine in young low-insulin-responders were different from those in the old ones. The low insulin responders are discussed in regard to prediabetes.     

毛细血管恢复率评估糖耐量异常者和2型糖尿病患者微循环功能

目的测定甲襞微循环毛细血管恢复率评价2型糖尿病和糖耐量异常患者的微血管舒张功能。方法2型糖尿病患者、糖耐量异常和糖耐量正常者各48例,微循环显微镜测定甲襞微循环毛细血管恢复率,比较微血管舒张功能差异。结果口服葡萄糖耐量试验正常者48例平均年龄（60.4±6.7）岁,平均毛细血管恢复率为（35.4±8.7）%;糖耐量异常者48例平均年龄（62.4±7.7）岁,平均毛细血管回复率（30.1±7.7）%比糖耐量正常者下降（P〈0.05）。2型糖尿病者48例平均年龄（64.3±8.1）岁,平均毛细血管恢复率（27.5±9.3）%,明显低于正常人和糖耐量异常者（P〈0.05）。在糖尿病患者,随病程延长,毛细血管恢复率呈递减趋势（P〈0.05）。结论糖耐量异常者已存在明显的微血管舒张功能降低,在糖尿病患者中这种微循环障碍进一步加重,提示糖代谢受损早期即出现微血管舒张功能障碍。     

Endocrine and metabolic responses after standardized moderate surgical trauma: influence of age and sex

Summary. The endocrine and metabolic responses to elective cholecystectomy and the influence of age and sex on this stress response were investigated in 21 patients, eight men and 13 women. The patients were divided into two groups, older (n=10) and younger (n=11) than 55 years respectively. Arterial plasma concentrations of catecholamines, cortisol and free fatty acids as well as serum insulin and arterial blood concentrations of glucose, lactate, glycerol, alanine and 3-hydroxybutyrate were measured preoperatively and 2, 24, 48, 72 and 96 h after the start of surgery. Oxygen uptake and CO₂ production were measured and respiratory quotient (RQ) was calculated. All hormones and metabolites except insulin and alanine were significantly elevated immediately after surgery. At 24 h plasma noradrenaline and blood glucose were still significantly increased. Serum insulin was increased at 24 and 48 h. Oxygen uptake and plasma cortisol were significantly elevated throughout the period studied and blood alanine was decreased from 2 to 72 h after surgery. The older group showed a significantly higher increase in noradrenaline and lactate, whereas women preoperatively as well as postoperatively had higher glycerol levels. At the end of the period studied women had higher FFA-levels. We conclude that cholecystectomy evokes a significant endocrine and metabolic response and that some of the variables studied are still significantly altered up to 4 days postoperatively. The influence of age and sex on this stress response is of minor importance.     

Muscle fiber characteristics in postmenopausal women with normal or impaired glucose tolerance.

OBJECTIVE: Muscle fiber characteristics are altered in type 2 diabetes. We studied whether these alterations also exist in impaired glucose tolerance (IGT) and whether they are determinants of insulin sensitivity and glucose tolerance in postmenopausal women. RESEARCH DESIGN AND METHODS: Percutaneous muscle biopsies from the vastus lateralis muscle were obtained from 77 postmenopausal women aged 57-59 years: 50 women with normal glucose tolerance (NGT) and 27 with IGT. The IGT group had a reduced insulin sensitivity compared with the NGT group (euglycemic-hyperinsulinemic clamp) (P = 0.003). RESULTS: The groups did not differ in muscle fiber composition, as judged by the percentage of type I, IIa, or IIx fibers. In contrast, the IGT group had increased size of the IIa (mean +/-SD 3,776+/-987 vs. 3,078+/-862 microm2, P = 0.002) and IIx fibers (2,730+/-1,037 vs. 2,253+/-672 microm2, P = 0.017). There was a trend for the capillary diffusion areas (the muscle area supplied by each capillary) to be larger in the IGT group for the IIa (1,132+/-286 vs. 1,013+/-240 microm2, P = 0.061) and IIx fibers (1,020+/-246 vs. 906+/-240 microm2, P = 0.058). In the entire group, insulin sensitivity correlated with the size of the type IIa fibers (r = -0.28, P = 0.013), but not with the percentages of muscle fiber types. In a multiple regression, insulin sensitivity was determined by body fat content and HDL cholesterol level, while the size of the IIa fibers was not included in the model. Glucose tolerance was independently predicted by the number of capillaries/type I fiber, as well as by insulin sensitivity and triglyceride levels. CONCLUSIONS: We conclude that although muscle fiber composition is not altered, women with IGT have larger type IIa and IIx muscle fibers and a trend for increased capillary diffusion areas for these fibers, compared with women with NGT. In the entire group, insulin sensitivity was determined mainly by body fat content, while muscle fiber capillarization may be of importance for glucose tolerance.     

Muscle metaboreflex contribution to resting limb haemodynamic control is preserved in older subjects

Ageing is associated with tonic elevations in basal sympathetic vasoconstrictor outflow to skeletal muscle and a parallel decline in vascular function. The purpose of this study was to test the hypothesis that older individuals exhibit attenuated calf vascular resistance (CVR) responses to muscle metaboreflex activation in comparison with young subjects. Fourteen young (mean +/- SD age 23 +/- 3 years) and 13 older (62 +/- 7 years) sedentary subjects participated in the study. To evaluate muscle metaboreflex, we measured heart rate, mean blood pressure (MBP), calf blood flow (CBF) (venous occlusion plethysmography) and CVR responses to static handgrip exercise at 30% of maximal voluntary contraction, followed by recovery with [postexercise circulatory occlusion, (PECO+)] or without (PECO-) circulatory occlusion. Mean BP and CVR increased significantly (ANOVA P<0.05) throughout exercise and remained elevated during PECO+ when compared with PECO- in both groups. There were no significant differences between the two groups in BP and CVR relative changes from baseline during the entire protocol in both trials. CBF responses were also similar in the young and older subjects, except for the first minute of exercise, where young subjects had higher CBF responses. Our results demonstrate that older subjects have similar BP and calf haemodynamic responses to static handgrip exercise and selective action of the muscle metaboreflex when compared with young subjects, compatible with preserved muscle metaboreflex contribution to resting limb haemodynamic control with ageing in humans.     

Concentrations of ionic, total, and bound fluoride in plasma.

We found no significant difference between the means for ionic, bound, and total fluoride concentrations in the plasma of male and female subjects of the same age, living in a community with fluoridated water. When results for the 264 fasting subjects were therefore combined according to age, they indicated that persons over 60 years of age have a significantly higher mean ionic (3.89 mumol/L) and total (6.58 mumol/L) fluoride concentration in plasma than do younger age groups. For younger age groups, means ranged from 2.74 to 3.05 mumol/L for ionic fluoride and from 4.74 to 5.58 mumol/L for total. The bound fluoride concentration was lower in individuals 21 to 30 years of age (1.89 mumol/L) than in older age groups (for whom means ranged from 2.42 to 2.68 mumol/L), but was not significantly different from that of individuals who were younger (2.21 mumol/L). A tendency for the mean ionic fluoride concentration to increase with age was noted, but the concentration was significantly higher than the preceding decade group only in those persons over 60 years of age.     

Decreased insulin sensitivity and muscle enzyme activity in elderly subjects

Skeletal muscle glycogen deposition, and the activation of muscle glycogen synthase and pyruvate dehydrogenase during a hyerinsulinaemic euglycaemic clamp have been measured in six young and six elderly males matched for body mass index, physical activity and diet. Clamp glucose requirement (insulin, 0.1 U kg-1 h-1) was significantly lower in the older subjects (8.0 +/- 0.4 mg kg-1 min-1) than in younger subjects (10.5 +/- 0.6 mg kg-1 min-1, P less than 0.02). Although the older subjects had a 6.5% decrease in lean body mass, clamp glucose requirement expressed per unit of lean body mass was also significantly decreased in the older subjects (10.2 +/- 0.5 vs. 12.4 +/- 0.6 mg kg-1 min-1, P less than 0.05). The increase in muscle glycogen with the clamp was decreased by 33% in the older subjects (elderly: 13.1 +/- 1.3 mg g-1 protein, young: 19.6 +/- 2.2 mg g-1 protein; P less than 0.05), and was strongly correlated with clamp glucose requirement (r = 0.72, P less than 0.01). Glucose-6-phosphate independent glycogen synthase activity increased significantly between fasting and the end of the clamps in both groups (P less than 0.001), but was lower at the end of the clamp in the older subjects (P less than 0.05). Glycogen synthase activity at the end of the clamp correlated with both clamp glucose requirement (r = 0.83, P less than 0.01) and muscle glycogen deposition (r = 0.73, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pancreatic beta-cell function evaluated by intravenous glucose and glucagon stimulation. A comparison between insulin and C-peptide to measure insulin secretion.

Insulin and C-peptide responses to 0.5 g kg-1 intravenous glucose and 1.0 mg glucagon were studied in 34 healthy subjects (age 19-78 years, mean 45). Fasting blood glucose (r = 0.59; p < 0.001) and glycosylated haemoglobin (r = 0.61; p < 0.001) increased with age, but not the initial C-peptide and insulin responses to the glucose infusion. However, the C-peptide response at 70 min (r = 0.36; p < 0.05), 80 min (r = 0.41; p < 0.05), and 90 min (r = 0.46; p < 0.01) after the glucose infusion correlated with age as well as both insulin (r = 0.42; p < 0.05) and C-peptide (r = 0.45; p < 0.05) responses to the glucagon injection. Reproducibility of insulin and C-peptide responses was evaluated by duplicate tests, separated 2-143 days in time, in 10 healthy subjects (age 19-48 years, mean 32 years) showing no significant differences in median within-subject variation between the initial (1 + 3 min) or overall (0-90 min area under curve) insulin (24% and 17%, respectively) and C-peptide (15% and 14%, respectively) responses to glucose, while the within-subject variation for the fasting values and the response to glucagon was higher (p < 0.05) for insulin (47% and 32%, respectively) than C-peptide (13% and 14%, respectively). Between-subject variation was also lower (p < 0.001) for C-peptide than for insulin. Thus, C-peptide measurements in healthy subjects are more reproducible than insulin measurements in determination of beta-cell function.     

Insulin and C-peptide levels, pancreatic beta cell function, and insulin resistance across glucose tolerance status in Thais

Impaired pancreatic beta cell function and insulin sensitivity are fundamental factors in the pathogenesis of type 2 diabetes; however, the predominant defect appears differ among ethnic groups. We conducted a cross-sectional study to evaluate the contribution of impaired beta cell function and insulin sensitivity at different stages of the deterioration of glucose tolerance in Thais. The study involved 420 urban Thais of both sexes, 43-84 years old. A 75-g oral glucose tolerance test was performed on all of the subjects. Indices of insulin resistance and beta cell function were calculated with the use of a homeostasis model assessment. The subjects were classified as having normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), combined IFG and IGT, or type 2 diabetes mellitus according to the American Diabetes Association (ADA) criteria. There were no differences between groups with regard to gender and age. The percentage of obesity was significantly greatest in the diabetic group. Fasting serum insulin and C-peptide levels progressively increased from the NGT to the diabetic subjects. Serum C-peptide was more strongly associated with newly diagnosed diabetes than insulin, and was an independent factor associated with newly diagnosed diabetic subjects. The insulin resistance index progressively increased when the glucose tolerance stage changed from NGT through diabetic subjects. Beta cell function did not change significantly in any other group compared to the NGT group. An increase in fasting serum C-peptide may be a risk factor for type 2 diabetes. Obesity and insulin resistance are the predominant features in the deterioration of glucose tolerance in Thais.     

动态血糖监测系统和胰岛素泵在脆性糖尿病患者围术期中的应用

目的：探讨动态血糖监测系统和胰岛素泵在围术期中控制脆性糖尿病患者血糖的效果。方法：将60例围术期脆性糖尿病患者随机分为3组：组1术前采用动态血糖监测系统与胰岛素泵治疗模式（CGMS＋CSII组）,组2术前采用单纯胰岛素泵治疗（CSII组）,组3术前采用胰岛素多次注射治疗（MDI组）,后两组采用指端血糖监测;比较3组治疗3d后的血糖控制情况、血糖达标率、平均血糖（MBG）、平均血糖波动幅度（MAGE）及低血糖次数。结果：治疗3d后CGMS＋CSII和CSII两组患者的空腹血糖、3餐后血糖、晚23：00血糖及凌晨3：00血糖均明显低于治疗前（P〈0.05）,血糖达标率分别为75.0%和60.0%,MDI组患者的空腹血糖及全日血糖稍低于治疗前,无显著性差异（P〉0.05）,血糖达标率仅为10.0%;胰岛素泵治疗3d后患者的MBG和MAGE较治疗前均明显下降（P〈0.05）,其中CGMS＋CSII组患者的MBG、MAGE均显著低于CSII组（P〈0.05）,MDI组MBG、MAGE较治疗前无明显下降（P〉0.05）;胰岛素治疗前CGMS＋CSII组患者1d发现低血糖次数多于CSII组和MDI组（P〈0.05）;治疗3d后CGMS组患者的低血糖次数低于治疗前（P〈0.05）,而CSII组和MDI组患者的低血糖次数高于治疗前（P〈0.05）。结论：胰岛素泵强化治疗可以快速稳定控制血糖,动态血糖检测系统能全面提供血糖水平的信息,及时发现和减少血糖波动及低血糖反应,与胰岛素泵在临床上联合应用更有利于脆性糖尿病患者围术期中的血糖控制达标。     

Insulin resistance is associated with reduced fasting and insulin-stimulated glycogen synthase phosphatase activity in human skeletal muscle.

Insulin-stimulated glycogen synthase activity in human skeletal muscle correlates with insulin-mediated glucose disposal rate (M) and is reduced in insulin-resistant subjects. We have previously reported reduced insulin-stimulated glycogen synthase activity associated with reduced fasting glycogen synthase phosphatase activity in skeletal muscle of insulin-resistant Pima Indians. In this study we investigated the time course for insulin stimulation of glycogen synthase and synthase phosphatase during a 2-h high-dose insulin infusion (600 mU/min per m2) in six insulin-sensitive caucasians (group S) and in five insulin-resistant Pima Indians (group R). Percutaneous muscle biopsies were obtained from the quadriceps femoris muscle after insulin infusion for 0, 10, 20, 40, and 120 min. In group S, insulin-stimulated glycogen synthase activity increased with time and was significantly higher than in group R. In group S, synthase phosphatase activity increased significantly by 25% at 10 min and then decreased gradually. No significant change in synthase phosphatase was seen in group R and activity was lower than group S at 0 to 20 min. These data suggest that a low basal synthase phosphatase activity and a defect in its response to insulin explain, at least in part, reduced insulin stimulation of skeletal muscle glycogen synthase associated with insulin resistance.     

Synthesis of muscle glycogen during recovery after prolonged severe exercise in diabetic and non-diabetic subjects.

Glycogen synthesis rate in skeletal muscle studied in six juvenile diabetic and six non-diabetic males ingesting a carbohydrate rich diet during 12 h of resting recovery after exhaustive bicycle exercise. The diabetic subjects took their regular insulin. Blood samples and muscle biopsies were obtained at rest prior to exercise, immediately after cessation of exercise and after 2,4,6.9 and 12 h of recovery. A marked decrease in muscle glycogn content was observed in response to exercise in both groups of subjects. Mean glycogen utilization rate was the same in the two groups. Glycogen synthesis rate during the first 4 h or recovery was 6.4 +/- 0.6 mmol glucosyl units/kg w.w./h in the diabetic subjects and 7.2 +/- 0.7 mmol glycosyl units/kg w.w./h in the non-diabetic subjects. During the next 8 h glycogen synthesis rate was approximately 1/3 of that being 2.0 +/- 0.3 and 2.4 +/- 0.5 mmol glucosyl units/kg w.w./h in the two groups respectively. Glycogen synthetase I-activity increased markedly in response to exercise in both groups of subjects. However, no differences were observed between the groups. No significant differences in muscle glucose 6-phosphate concentrations were observed between the two groups. Plasma glucose levels were significantly higher in the diabetic than in the non-diabetic subjects. It is concluded that glycogen synthesis during recovery following prolonged severe exercise can proceed at the same rate in diabetic subjects taking their regular insulin as in non-diabetic subjects.     

Evaluation of insulin release and relative peripheral resistance with use of the oral glucose tolerance test: a study in subjects with normoglycaemia, glucose intolerance and non-insulin-dependent diabetes mellitus

With use of 75 g oral glucose tolerance tests (OGTTs), insulin release and relative peripheral resistance were evaluated in groups of normoglycaemic subjects, subjects with glucose intolerance (GI) and patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin release was expressed as the total area under the insulin curve (AUCI) and as the area under the insulin curve above the fasting insulin level (delta AUCI). The insulin response to glucose was expressed as the ratio of the area under the insulin curve to that of the glucose curve above fasting levels (delta AUCI/delta AUCG). The glucose uptake rate during the OGTT (M) was measured as the difference between the glucose load and the increase of the amount of glucose in the glucose space after, compared to before, the OGTT. The relative peripheral resistance against glucose uptake promoting factors (rel-R) was expressed as 1/M. With application of these indices in the non-obese groups, there was an increased mean total insulin release (AUCI, delta AUCI) while the mean insulin response to glucose (delta AUCI/delta AUCG) was decreased in GI-subjects compared with normoglycaemic subjects. The mean relative peripheral resistance (rel-R) was higher in GI-subjects than in normoglycaemics. Mean values of AUCI and delta AUCI were decreased (lower than in the normoglycaemics, NS), mean values of delta AUCI/delta AUCG were further decreased and mean values of rel-R were further increased in the NIDDM-groups compared with the GI-group. Insulin release was delayed in GI and NIDDM. Obese normal and obese GI-subjects with similar rel-R values as the corresponding non-obese normal and non-obese GI-subjects, had higher mean values of insulin release than the non-obese counterparts. Thus, it seemed possible to use a technique in general use, the OGTT, with a partly new approach to simultaneously obtain indices for insulin release and relative peripheral resistance, which may have clinical applicability.     

Age-related reductions in appendicular skeletal muscle mass: association with habitual aerobic exercise status

Appendicular skeletal muscle mass decreases with advancing age, and this is thought to be a key factor for reductions in functional independence in the elderly. We determined the potential modulatory influence of regular aerobic exercise on the age-related reductions in appendicular muscle mass. In the present cross-sectional study, we studied a total of 131 healthy men aged 20-79 years. For at least the previous 2 years subjects were either sedentary or endurance-trained. Appendicular skeletal muscle mass was measured using dual-energy X-ray absorptiometry. There were no significant group differences in height. Body mass and body surface area were lower in endurance-trained compared with sedentary men (P<0.05). In general, body fat increased with age in both groups, but was lower in endurance-trained compared with sedentary men at any age group (P<0.05). Lean body mass and maximal oxygen consumption decreased with age (P<0.05). Irrespective of expression (absolute, relative to body surface area, or relative to body mass), arm, leg, and total limb muscle mass generally decreased with age. Absolute appendicular muscle mass was not different between the two activity groups. When expressed relative to body mass or body surface area, appendicular muscle mass in the endurance-trained middle-aged and older men was significantly higher than their sedentary peers. The rate of decline in appendicular muscle mass with age was similar between the two activity groups. The results of the present cross-sectional study indicate that endurance-trained men had significantly higher appendicular skeletal muscle mass relative to body mass or body size compared with their sedentary peers. This may contribute, at least in part, to the lower incidence of functional disability observed in middle-aged and older men who exercise regularly.     

Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men.

Insulin action and obesity are both correlated with the density of muscle capillary supply in humans. Since the altered muscle anatomy in the obese might affect interstitial insulin concentrations and reduce insulin action, we have cannulated peripheral lymphatic vessels in lean and obese males, and compared peripheral lymph insulin concentrations with whole body glucose uptake during a euglycemic, hyperinsulinemic clamp. Lymph insulin concentrations in the lower limb averaged only 34% of arterial insulin concentrations during 150 min of insulin infusion. Obese subjects had the highest arterial (P < or = 0.0001) and lymph insulin (P < 0.005) concentrations, but the lowest glucose uptake rates (P < 0.002). In contrast to the initial steep rise then plateau of arterial insulins, both lymph insulin and whole body glucose uptake rates rose slowly and did not consistently reach a plateau. In each individual, the glucose uptake closely correlated with peripheral lymphatic insulin concentrations (mean r2 = 0.95). The coupling between glucose uptake and lymph insulin (glucose uptake/pmol insulin) was much steeper in lean subjects than in the obese (P < or = 0.0001). These results indicate that even if insulin diffusion into tissues is rate limiting for insulin action, a tissue defect rather than an insulin diffusion defect causes insulin resistance in obese subjects.     

A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes

OBJECTIVE: To compare the efficacy and safety of continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI) in older adults with insulin-treated type 2 diabetes and to assess treatment satisfaction and quality of life. RESEARCH DESIGN AND METHODS: Adults (n = 107) > or =60 years of age (mean age 66 years) with insulin-treated type 2 diabetes (mean duration 16 years, BMI 32 kg/m(2), and HbA(1C) [A1C] 8.2%) were randomized to CSII (using insulin lispro) or MDI (using insulin lispro and insulin glargine) in a two-center, 12-month, prospective, randomized, controlled clinical trial. Efficacy was assessed with A1C, safety by frequency of hypoglycemia, and treatment satisfaction and quality of life with the Diabetes Quality of Life Clinical Trial Questionnaire and the 36-item short-form health survey, version 2. RESULTS: Forty-eight CSII subjects (91%) and 50 MDI subjects (93%) completed the study. Mean A1C fell by 1.7 +/- 1.0% in the CSII group to 6.6% and by 1.6 +/- 1.2% in the MDI group to 6.4%. The difference in A1C between treatment groups was not statistically significant (P = 0.20). Eighty-one percent of CSII subjects and 90% of MDI subjects experienced at least one episode of minor (self-treated) hypoglycemia (P = 0.17), and three CSII and six MDI subjects experienced severe hypoglycemia (P = 0.49). Rates of severe hypoglycemia were similarly low in the two groups (CSII 0.08 and MDI 0.23 events per person-year, P = 0.61). Weight gain did not differ between groups (P = 0.70). Treatment satisfaction improved significantly with both CSII and MDI (P < 0.0001), and the difference between groups was not statistically significant (P = 0.58). CONCLUSIONS: In older subjects with insulin-treated type 2 diabetes, both CSII and MDI achieved excellent glycemic control with good safety and patient satisfaction.