Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.     

Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects

Summary Our study investigates short- and long-term effects of infusion of non-esterified fatty acids (NEFA) on insulin secretion in healthy subjects. Twelve healthy individuals underwent a 24-h Intralipid (10% triglyceride emulsion) infusion at a rate of 0.4 ml/min with a simultaneous infusion of heparin (a bolus of 200 U followed by 0.2 U/min per kg body weight). After an overnight fast (baseline), at 6 and at 24 h of Intralipid infusion and 24 h after Intralipid discontinuation (recovery test), all subjects underwent an intravenous glucose tolerance test (iv-GTT) (25 g of glucose/min). Intralipid infusion caused a threefold rise in plasma NEFA concentrations with no difference between the 6- and the 24-h concentrations. Compared to baseline acute insulin response (AIR) (AIR=63±8 mU/l), short-term (6-h) Intralipid infusion was associated with a significant increase in AIR (86±12 mU/l p<0.01); in contrast, long-term (24-h) Intralipid delivery was associated with inhibition of AIR (31±5 mU/l) compared to baseline (p<0.001) and to the 6-h (p<0.03) triglyceride emulsion infusion. Intralipid infusion was associated with a progressive and significant decline in respiratory quotient (RQ). A positive correlation between changes in fasting plasma NEFA concentrations and AIR at the 6-h infusion (r=0.89 p<0.001) was found. In contrast, at the end of the Intralipid infusion period, changes in plasma NEFA concentrations and AIR were negatively correlated (r=–0.87 p<0.001). The recovery test showed that fasting plasma NEFA concentrations, RQ and AIR had returned to baseline values. In the control study (n=8) 0.9% NaCl infusion did not mimick the effect of Intralipid. In conclusion, our study demonstrates that short- and long-term exposures of beta cells to high plasma NEFA concentrations have opposite effects on glucose-induced insulin secretion.Abbreviations NEFA Non-esterified fatty acids - ivGTT intravenous glucose tolerance test - AIR acute insulin response - NIDDM non-insulin-dependent diabetes mellitus     

Improvement of cardiovascular risk factors in patients with type 2 diabetes after long-term continuous subcutaneous insulin infusion

BACKGROUND: The effects of long-term continuous subcutaneous insulin infusion (CSII) on cardiovascular risk factors such as hyperglycaemia, dyslipidaemia, and proinflammatory cytokine levels have not been assessed so far in type 2 diabetes. METHODS: We analysed the levels of HbA(1c), serum lipids, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) at 0, 2, and 30 weeks after CSII in 15 patients with type 2 diabetes (mean age, 53.3+/-10.1 years; disease duration, 9.4+/-5.3 years) without previous history of major cardiovascular events. RESULTS: At week 30, CSII significantly lowered HbA(1c) by 5.0+/-0.9% compared to baseline (7.9+/-1.9%, p<0.001) and improved high-density lipoprotein cholesterol (HDLc; 1.09+/-0.16 at baseline vs 1.25+/-0.15 mmol/L at week 30; p<0.05) and low-density lipoprotein cholesterol (LDLc)/HDLc ratios (2.8+/-1.4 at baseline vs 2.2+/-0.9 at week 30; p<0.05). CSII also decreased the proportion of patients with dyslipidaemia at week 30. At baseline, TNF-alpha and IL-6 levels were up-regulated (2.65+/-4.04 and 2.82+/-1.81 pg/mL, respectively) compared to the normal control (p<0.01 and p<0.05, respectively); however, cytokine levels decreased significantly at week 30 (1.44+/-2.25 and 1.99+/-1.05 pg/mL, respectively; p=NS vs control). CONCLUSIONS: Long-term CSII alone decreased cardiovascular risk factors in poorly controlled type 2 diabetes, suggesting that the synchronization of sufficient insulin peaks with meal ingestion and continuous pulsatile infusion of basal insulin corrects metabolic derangements.     

Insulin secretion and insulin action in Taiwanese with type 2 diabetes

In contrast to the United State, type 2 diabetes appears to be a common occurrence in non-obese Asians. In order to evaluate the possibility that this epidemiologic difference was indicative of a basic metabolic phenomenon, estimates of insulin secretion and insulin action were generated in 32 Chinese males, 16 with type 2 diabetes and 16 with normal glucose tolerance. Half of the individuals in each diagnostic category were obese (body mass index greater than 28 kg/m2) and half were non-obese (less than 26 kg/m2). Plasma glucose responses to a 75-g oral glucose challenge were significantly higher in patients with type 2 diabetes, but did not vary significantly within either group as a function of obesity. Plasma insulin concentrations were lower than normal when patients with type 2 diabetes were compared to their weight-matched controls. In addition, the absolute insulin values also varied as a function of body weight, with higher plasma insulin concentrations observed in the obese individuals. Insulin action was estimated by determination of the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations during the last 60 min of a continuous 180-min intravenous infusion of somatostatin, crystalline insulin, and glucose. Under these conditions endogenous insulin secretion is suppressed, SSPI concentrations are similar in all individuals, and SSPG concentrations provide a quantitative estimate of insulin-stimulated glucose disposal. The results of these studies indicated that patients with type 2 diabetes had significantly elevated SSPG concentrations as compared to normals, and this was true whether the diabetic subjects were obese or non-obese.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin sensitivity, glucose effectiveness, and free fatty acid dynamics after human islet transplantation for type 1 diabetes

CONTEXT: Islet transplantation results in impaired insulin secretion, but whether defects in insulin sensitivity contribute to impaired glucose disposal after islet transplantation under modern immunosuppression is not known. OBJECTIVE: Our objective was to evaluate insulin sensitivity after islet transplantation performed under tacrolimus-based immunosuppression that used minimal steroids. SETTING: This study was conducted at the University of Pennsylvania General Clinical Research Center. PARTICIPANTS: Eight islet transplant recipients, six type 1 diabetic (T1D), and 10 nondiabetic control subjects participated. Intervention: We performed an insulin-modified frequently sampled iv glucose tolerance test to measure insulin sensitivity (S(I)), glucose effectiveness, and free fatty acid (FFA) dynamics. RESULTS: S(I) was significantly greater in the islet transplant and control groups, compared with the T1D group (P < 0.05 for both comparisons). Glucose effectiveness was not significantly different across all three groups but was lower by trend in the T1D and islet transplant groups, compared with the control group (P = 0.07 overall ANOVA). FFA levels suppressed normally in the transplant recipients, but the timing and magnitude of FFA suppression were significantly impaired in the T1D group, compared with the islet transplant and control groups (P < 0.05 for all comparisons). The acute insulin response to glucose and the disposition index (D(I) = acute insulin response to glucose x S(I)) were significantly lower in the islet transplant group, compared with the control group (P < 0.05 for all comparisons). CONCLUSIONS: These data suggest that even modest restoration of insulin secretion in islet transplant recipients may result in improved insulin sensitivity and FFA dynamics.     

Insulin use and increased risk of mortality in type 2 diabetes: a cohort study

Aim: To compare population‐based rates of all‐cause and cardiovascular (CV) mortality in newly treated patients with type 2 diabetes according to levels of insulin exposure. Methods: Using the administrative databases of Saskatchewan Health, 12272 new users of oral antidiabetic therapy were identified between 1991 and 1996 and grouped according to cumulative insulin exposure based on total insulin dispensations per year: no exposure (reference group); low exposure (0 to <3); moderate exposure (3 to <12) and high exposure (≥12). Time‐varying multivariable Cox proportional hazards models were used to examine the relationship between insulin exposure and all‐cause, CV‐related and non‐vascular mortality after adjustment for demographics, medications and comorbidities. Results: Average age was 65 (s.d. 13.9) years, 45% were female, and mean follow‐up was 5.1 (s.d. 2.2) years. In total, 1443 (12%) subjects started insulin, and 2681 (22%) deaths occurred. The highest mortality rates were in the high exposure group; 95 deaths/1000 person‐years compared with 40 deaths/1000 person‐years in the no exposure group [unadjusted hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.96–2.73]. After adjustment, we observed a graded risk of mortality associated with increasing exposure to insulin: low exposure [adjusted HR (aHR): 1.75; 95% CI: 1.24–2.47], moderate exposure (aHR: 2.18; 1.82–2.60) and high exposure (aHR: 2.79; 2.36–3.30); p = 0.005 for trend. Analyses restricted to CV‐related (p = 0.042 for trend) and non‐vascular (p = 0.004 for trend) mortality showed virtually identical results. Conclusions: We observed a significant and graded association between mortality risk and insulin exposure level in an inception cohort of patients with type 2 diabetes that persisted despite multivariable adjustment.     

Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes

Aims/hypothesis Intramyocellular lipids, including ceramide, a second messenger in the sphingomyelin signalling pathway, might contribute to the development of insulin resistance. The aim of our study was to assess parameters of the skeletal muscle sphingomyelin signalling pathway in men at risk of developing type 2 diabetes. Methods We studied 12 lean (BMI < 25 kg/m²) men without a family history of diabetes (control group), 12 lean male offspring of type 2 diabetic patients, and 21 men with overweight or obesity comprising 12 with NGT (obese-NGT) and nine with IGT (obese-IGT). A euglycaemic-hyperinsulinaemic clamp and a biopsy of vastus lateralis muscle were performed. Ceramide, sphingomyelin, sphinganine and sphingosine levels and sphingomyelinase and ceramidase activities were measured in muscle. Muscle diacylglycerol and triacylglycerol levels were estimated in a subgroup of 27 men (comprising men from all the above groups). Results Compared with the control group, the lean offspring of diabetic patients and the men with overweight or obesity showed lower insulin sensitivity (all p < 0.005) and a greater muscle ceramide level (all p < 0.01). The obese-IGT group had lower insulin sensitivity (p = 0.0018) and higher muscle ceramide (p = 0.0022) than the obese-NGT group. There was lower muscle sphingosine level and alkaline ceramidase activity in offspring of diabetic patients (p = 0.038 and p = 0.031, respectively) and higher sphinganine level in the obese-NGT (p = 0.049) and obese-IGT (p = 0.002) groups than in the control group. Muscle sphingomyelin was lower (p = 0.0028) and neutral sphingomyelinase activity was higher (p = 0.00079) in the obese-IGT than in the obese-NGT group. Muscle ceramide was related to insulin sensitivity independently of other muscle lipid fractions. Conclusions/interpretations Ceramide accumulates in muscle of men at risk of developing type 2 diabetes.     

老老年高血压合并2型糖尿病患者游离脂肪酸水平分析

目的：研究老老年高血压患者2型糖尿病与血清游离脂肪酸之间的关系。方法：纳入老老年原发性高血压患者152例,其中伴有2型糖尿病者74例,为1组;非2型糖尿病者78例,为2组;两组患者均检测血脂,比较两组血脂水平的差异。结果：2组患者比较,BMI:1组（28.73±5.49）＞2组（23.21±5.83）,空腹血糖：1组（7.01±2.71）＞2组（5.30±0.85）,游离脂肪酸水平：1组（0.62±0.32）＞2组（0.51±0.28）,总胆固醇：1组（4.16±1.04）＞2组（3.87±0.93）,甘油三酯：1组（1.56±0.84）＞2组（1.31±0.66）,高密度脂蛋白：1组（1.06±0.25）＞2组（1.22±0.32）,极低密度脂蛋白：1组（0.35±0.29）＞2组（0.27±0.15）,APOA1：1组（1.10±0.17）＜（1.17±0.19）,脂蛋白A：（14.64±15.64）＜（21.89± 21.46）,均P＜0.05,差异有统计学意义;Spearman相关性分析显示：BMI（r=0.468,p=0.002）、游离脂肪酸（r=0.147,p=0.027）、总胆固醇（r=0.147,p=0.028）、高密度脂蛋白（r=-0.261,p=0.000）、VLDL（r=0.148,p=0.026）、APOA1（r=-0.162,p=0.014）、脂蛋白A（r=-0.219,p=0.001）均与2型糖尿病存在相关性。二元Logistic回归分析显示,血清游离脂肪酸水平与老老年高血压合并2型糖尿病关系最为密切。结论：老老年高血压合并2型糖尿病患者脂质代谢紊乱更加严重,应予以足够的重视,而血清游离脂肪酸水平或许可以作为一干预靶点和预测指标。     

HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion

Aims/hypothesis

We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona.

Methods

Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits.

Results

The A allele at rs9268852, which tags HLA-DRB1*02(1602), was associated both with higher HLA-DRB1 mRNA expression (n?=?133, p?=?4.27?×?10^?14) and decreased risk of type 2 diabetes (n?=?3,265, OR 0.723, p?=?0.002). Among persons with normal glucose tolerance (n?=?266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p?=?0.005), higher mean 30?min insulin concentration during an oral glucose tolerance test (p?=?0.017) and higher body fat percentage (p?=?0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity.

Conclusions/interpretation

HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.     

2型糖尿病患者游离脂肪酸水平与认知功能障碍的关系

目的探讨2型糖尿病(T2DM)患者游离脂肪酸(FFA)水平与认知功能障碍的关系。方法选择183例患者,根据口服葡萄糖耐量试验结果分为T2DM组80例、葡萄糖耐量异常(IGT)组45例和葡萄糖耐量正常(NGT)组58例,行空腹游离脂肪酸(fFFA)、2h游离脂肪酸(2hFFA)和蒙特利尔认知评估量表(MoCA)测定。结果T2DM组患者fFFA、2hFFA高于NGT组和IGT组[(0.65±0.30)mmol/L vs(0.55±0.27)mmol/L和(0.43±0.19)mmol/L,P=0.001,(0.31±0.15)mmol/L vs(0.22±0.14)mmol/L和(0.11±0.13)mmol/L,P=0.000],MoCA评分低于NGT组和IGT组[(16.01±11.62)分vs(22.34±6.42)分和(27.21±2.83)分,P=0.000];fFFA、2hFFA与MoCA评分呈负相关(r=-0.891,-0.469,P<0.05)。结论 fFFA、2hFFA与胰岛素抵抗及糖尿病患者认知功能障碍存在一定的相关性。     

Insulin resistance in type 2 diabetes: role of fatty acids

Insulin resistance is one of the key factors responsible for hyperglycaemia in type 2 diabetes and can result in a number of metabolic abnormalities associated with cardiovascular disease (insulin resistance syndrome), even in the absence of overt diabetes. The mechanisms involved in the development of insulin resistance are multifactorial and are only partly understood, but increased availability of free fatty acids (FFAs) is of particular importance for the liver and skeletal muscle. The role of FFAs in type 2 diabetes is most evident in obese patients who have several abnormalities in FFA metabolism. Because of a mass effect, the release of FFAs from the total adipose tissue depot to the blood stream is increased and the high concentration of circulating FFAs impairs muscle uptake of glucose by competitive inhibition. In upper-body obesity, which predisposes individuals to type 2 diabetes, the rate of lipolysis is accelerated in visceral adipose tissue. This results in a selective increase in FFA mobilisation to the portal vein, which connects visceral fat to the liver. A high 'portal' FFA concentration has undesirable effects on the liver, resulting in dyslipidaemia, hyperinsulinaemia, hyperglycaemia and hepatic insulin resistance. Recently, a new class of antidiabetic agents, the thiazolidinediones (TZDs) or 'glitazones' has been developed. A prominent effect of these agents is the lowering of circulating FFA levels and it is believed, but not yet proven, that this interaction with FFAs constitutes a major mechanism behind the glucose-lowering effect of the TZDs.     

The effect of high-dose simvastatin on free fatty acid metabolism in patients with type 2 diabetes mellitus

Statins improve all major lipid fractions, reduce coronary heart disease risk, and may have a minor effect on glucose tolerance. A reduction in free fatty acid flux and concentrations could be partly responsible for these effects. We measured nocturnal and postprandial plasma palmitate concentrations and rate of appearance (R(a)) on 2 occasions in 12 obese dyslipidemic subjects with type 2 diabetes mellitus, using a single-blind, crossover format (placebo followed by simvastatin, 80 mg/d), and also on 1 occasion in 6 untreated control subjects. The diabetic subjects had increased average nocturnal (127+/-13 vs 80+/-10 micromol/L, P<.05) and 2-hour postprandial (49+/-6 vs 17+/-2 micromol/L, P<.001) palmitate concentrations, as well as increased nocturnal (31.6+/-3.7 vs 19.5+/-3.7 mmol/m(2) over 9 hours, P<.05) and postprandial (11.5+/-3.7 vs 5.5+/-3.7 mmol/m(2) every 4 hours, P<.005) integrated palmitate R(a) compared to normal controls. High-dose simvastatin reduced serum triglycerides by 35% but had no effect on plasma palmitate concentrations or R(a). These results suggest that the triglyceride-lowering effect of statins is not mediated through an effect on FFA metabolism.     

Insulin secretion and insulin action related to the serum phospholipid fatty acid pattern in healthy men

In order to decide whether the phospholipid fatty acid pattern is related to variables determining glucose tolerance, 11 healthy volunteers with normal glucose tolerance were studied. The relationship was evaluated between the proportions of individual fatty acids (FA) in serum phospholipids and (1) insulin secretion, determined by fasting and postglucose plasma insulin levels, and (2) in vivo insulin action, assessed as metabolic clearance rates of glucose during euglycemic clamp studies at two insulin concentrations of approximately 70 microU/mL (MCRglu70) and 500 microU/mL (MCRglu500). It was found that both insulin secretion and insulin action are significantly related to the ratio of omega-6 class essential FA to saturated FA in serum phospholipids. An increase of this ratio is associated with a decrease in total insulin response (r = -0.84, P less than .01), and an increase in MCRglu70 (r = .66, P less than .05) and MCRglu500 (r = .82, P less than .01). The data presented support the hypothesis that phospholipid FA composition might play a role in blood glucose regulation.     

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

Aims/hypothesis Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes. Materials and methods Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry. MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function. Results Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice. Conclusions/interpretation Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory defects reflect an early stage of beta cell dysfunction. Electronic supplementary material Electronic supplementary material is available for this article at Asghar and Chan contributed equally to this work. An erratum to this article can be found at