Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes.

We examined the hypothesis that an excess accumulation of intramuscular lipid (IMCL) is associated with insulin resistance and that this may be mediated by the oxidative capacity of muscle. Nine sedentary lean (L) and 11 obese (O) subjects, 8 obese subjects with type 2 diabetes mellitus (D), and 9 lean, exercise-trained (T) subjects volunteered for this study. Insulin sensitivity (M) determined during a hyperinsulinemic (40 mU x m(-2)min(-1)) euglycemic clamp was greater (P < 0.01) in L and T, compared with O and D (9.45 +/- 0.59 and 10.26 +/- 0.78 vs. 5.51 +/- 0.61 and 1.15 +/- 0.83 mg x min(-1)kg fat free mass(-1), respectively). IMCL in percutaneous vastus lateralis biopsy specimens by quantitative image analysis of Oil Red O staining was approximately 2-fold higher in D than in L (3.04 +/- 0.39 vs. 1.40 +/- 0.28% area as lipid; P < 0.01). IMCL was also higher in T (2.36 +/- 0.37), compared with L (P < 0.01). The oxidative capacity of muscle determined with succinate dehydrogenase staining of muscle fibers was higher in T, compared with L, O, and D (50.0 +/- 4.4, 36.1 +/- 4.4, 29.7 +/- 3.8, and 33.4 +/- 4.7 optical density units, respectively; P < 0.01). IMCL was negatively associated with M (r = -0.57, P < 0.05) when endurance-trained subjects were excluded from the analysis, and this association was independent of body mass index. However, the relationship between IMCL and M was not significant when trained individuals were included. There was a positive association between the oxidative capacity and M among nondiabetics (r = 0.37, P < 0.05). In summary, skeletal muscle of trained endurance athletes is markedly insulin sensitive and has a high oxidative capacity, despite having an elevated lipid content. In conclusion, the capacity for lipid oxidation may be an important mediator of the association between excess muscle lipid accumulation and insulin resistance.     

Intensive insulin therapy in critically ill hospitalized patients: making it safe and effective

Intensive insulin therapy (IIT) for hyperglycemia in critically ill patients has become a standard practice. Target levels for glycemia have fluctuated since 2000, as evidence initially indicated that tight glycemic control to so-called normoglycemia (80–110 mg/dl) leads to the lowest morbidity and mortality without hypoglycemic complications. Subsequent studies have demonstrated minimal clinical benefit combined with greater hypoglycemic morbidity and mortality with tight glycemic control in this population. The consensus glycemic targets were then liberalized to the mid 100s (mg/dl).Handheld POC blood glucose (BG) monitors have migrated from the outpatient setting to the hospital environment because they save time and money for managing critically ill patients who require IIT. These devices are less accurate than hospital-grade POC blood analyzers or central laboratory analyzers.Three questions must be answered to understand the role of IIT for defined populations of critically ill patients: (1) How safe is IIT, with various glycemic targets, from the risk of hypoglycemia? (2) How tightly must BG be controlled for this approach to be effective? (3) What role does the accuracy of BG measurements play in affecting the safety of this method? For each state of impaired glucose regulation seen in the hospital, such as hyperglycemia, hypoglycemia, or glucose variability, the benefits, risks, and goals of treatment, including IIT, might differ.With improved accuracy of BG monitors, IIT might be rendered even more intensive than at present, because patients will be less likely to receive inadvertent overdosages of insulin. Greater doses of insulin, but with dosing based on more accurate glucose levels, might result in less hypoglycemia, less hyperglycemia, and less glycemic variability.     

Mediation of beta-endorphin in exercise-induced improvement in insulin resistance in obese Zucker rats

BACKGROUND: Aerobic exercise including treadmill running has long been used to successfully treat and/or prevent insulin resistance and type-2 diabetes. Increase of plasma beta-endorphin is observed with exercise. The present study was designed to clarify the role of endogenous beta-endorphin in exercise-induced improvement in insulin resistance. METHODS: We used a moderate exercise program consisting of treadmill running at 20 m/min and 0% grade for 1 h/day, 7 days/week, for 8 weeks. Plasma glucose concentration was assessed by the glucose oxidase method. The enzyme-linked immunosorbent assay was performed to quantify the plasma level of beta-endorphin-like immunoreactivity (BER). The glucose disposal rate (GDR) was measured by the hyperinsulinemic euglycemic clamp technique. Changes of the insulin signaling in isolated soleus muscle were then detected by immunoprecipitation and immunoblotting. RESULTS: An increase of plasma BER in parallel with the reduction of plasma glucose was obtained in exercise-trained obese Zucker rats. Different from a marked reduction in sedentary obese rats, the value of insulin-stimulated GDR obtained from the exercised obese rats was reversed to near that of the sedentary lean group, eight weeks after the last period of exercise. This effect of exercise was inhibited by naloxone or naloxonazine at doses sufficient to block opioid micro-receptors. Signaling-related defects in the soleus muscle of sedentary obese Zucker rats, which impaired glucose transporter subtype 4 (GLUT 4), included decreased phosphorylation of insulin receptor substrate (IRS)-1, as well as an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3 kinase) and Akt serine phosphorylation. In contrast, exercise training failed to modify the levels of insulin receptor (IR), IRS-1, and IR tyrosine autophosphorylation in obese Zucker rats. CONCLUSION: Enhanced insulin sensitivity via exercise training might be mediated by endogenous beta-endorphin through an increase of postreceptor insulin signaling related to the IRS-1-associated PI3-kinase step that leads to the enhancement of GLUT 4 translocation and improved glucose disposal in obese Zucker rats.     

Exercise at anaerobic threshold intensity and insulin secretion by isolated pancreatic islets of rats

To evaluate the effect of acute exercise and exercise training at the anaerobic threshold (AT) intensity on aerobic conditioning and insulin secretion by pancreatic islets, adult male Wistar rats were submitted to the lactate minimum test (LMT) for AT determination. Half of the animals were submitted to swimming exercise training (trained), 1 h/day, 5 days/week during 8 weeks, with an overload equivalent to the AT. The other half was kept sedentary (sedentary). At the end of the experimental period, the rats were submitted to an oral glucose tolerance test and to another LMT. Then, the animals were sacrificed at rest or immediately after 20 minutes of swimming exercise at the AT intensity for pancreatic islets isolation. At the end of the experiment mean workload (% bw) at AT was higher and blood lactate concentration (mmol/L) was lower in the trained than in the control group. Rats trained at the AT intensity showed no alteration in the areas under blood glucose and insulin during OGTT test. Islet insulin content of trained rats was higher than in the sedentary rats while islet glucose uptake did not differ among the groups. The static insulin secretion in response to the high glucose concentration (16.7 mM) of the sedentary group at rest was lower than the sedentary group submitted to the acute exercise and the inverse was observed in relation to the trained groups. Physical training at the AT intensity improved the aerobic condition and altered insulin secretory pattern by pancreatic islets.     

Exercise at anaerobic threshold intensity and insulin secretion by isolated pancreatic islets of rats

To evaluate the effect of acute exercise and exercise training at the anaerobic threshold (AT) intensity on aerobic conditioning and insulin secretion by pancreatic islets, adult male Wistar rats were submitted to the lactate minimum test (LMT) for AT determination. Half of the animals were submitted to swimming exercise training (trained), 1 h/day, 5 days/week during 8 weeks, with an overload equivalent to the AT. The other half was kept sedentary (sedentary). At the end of the experimental period, the rats were submitted to an oral glucose tolerance test and to another LMT. Then, the animals were sacrificed at rest or immediately after 20 minutes of swimming exercise at the AT intensity for pancreatic islets isolation. At the end of the experiment mean workload (% bw) at AT was higher and blood lactate concentration (mmol/L) was lower in the trained than in the control group. Rats trained at the AT intensity showed no alteration in the areas under blood glucose and insulin during OGTT test. Islet insulin content of trained rats was higher than in the sedentary rats while islet glucose uptake did not differ among the groups. The static insulin secretion in response to the high glucose concentration (16.7 mM) of the sedentary group at rest was lower than the sedentary group submitted to the acute exercise and the inverse was observed in relation to the trained groups. Physical training at the AT intensity improved the aerobic condition and altered insulin secretory pattern by pancreatic islets.     

Effect of intensive insulin therapy on insulin sensitivity in the critically ill

CONTEXT: Hyperglycemia and hyperinsulinemia are common in intensive care unit (ICU) patients and relate to illness severity. Intensive insulin therapy (IIT) to maintain normoglycemia reduces morbidity and mortality. Blood glucose control explains this benefit because a high insulin dose is associated with adverse outcome. Mitogenic insulin effects could theoretically explain this link. OBJECTIVE: To investigate further the association between insulin dose and adverse outcome, we studied the effect of IIT on circulating insulin levels, markers of insulin sensitivity, and the metabolic and mitogenic insulin signaling molecules in key tissues. DESIGN: This is a subanalysis of a large randomized, controlled study. SETTING: The study was performed in a university hospital surgical ICU. PATIENTS: A total of 339 critically ill patients, treated in ICU for at least a week, were included in this subanalysis. INTERVENTION: Strict normoglycemia with IIT compared with conventional insulin therapy was performed. RESULTS: Severalfold higher insulin doses than with conventional insulin therapy were required to maintain normoglycemia with IIT. However, serum insulin levels were only transiently higher with IIT, despite the much lower blood glucose levels. IIT normalized the elevated serum C-peptide levels and increased circulating adiponectin levels. The metabolic insulin signal was increased by IIT in muscle, but not in liver. The mitogenic insulin signal in either tissue was not affected by IIT. CONCLUSIONS: Normoglycemia can be maintained in ICU patients without a sustained further elevation of insulinemia. Together with the increased adiponectin levels, this finding suggests that IIT may improve insulin sensitivity. Skeletal muscle, but not liver, revealed an increased metabolic insulin signal. The therapy did not impose mitogenic risk in these tissues.     

Effect of short-term intensive insulin therapy on the incretin response in early type 2 diabetes

AimsShort-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes.MethodsIn this study, 63 patients (age 59 ± 8.3 years, baseline A1c 6.8 ± 0.7%, diabetes duration 3.0 ± 2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR).ResultsAs expected, comparing the post-therapy oral glucose tolerance test to that at baseline, IIT increased ISSI-2 (P = 0.02), decreased HOMA-IR (P < 0.001), and reduced AUC_glucagon (P < 0.001). Of note, however, IIT had no significant impact on AUC_GLP-1 (P = 0.24) and reduced AUC_GIP (P = 0.02).ConclusionDespite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP-1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion.     

The response to short-term intensive insulin therapy in type 2 diabetes

Aim: Although a short course of intensive insulin therapy (IIT) can improve beta-cell function and glycaemic control in most patients with newly diagnosed type 2 diabetes (T2DM), the impact of this intervention in diabetes of longer duration has not been carefully studied. Thus, we sought to evaluate the effect of short-term IIT in patients with established T2DM.
Methods: Thirty-four patients, with diabetes of mean 5.9 ± 6.6 years duration, underwent 4–8 weeks of IIT, with 4-h meal test administered at baseline and at 1 day post-IIT. A positive clinical response was defined as fasting glucose < 7.0 mmol/l off any antidiabetic therapy at the latter test.
Results: A positive response was achieved in 68% (n = 23) of the subjects. At baseline meal test, the responders had lower glucose levels than the non-responders from 120 to 240 min (all timepoints p ≤ 0.0008) and higher late incremental area-under-the-C-peptide-curve (AUC_Cpep), particularly from 60 to 150 min (all p < 0.005). Beta-cell function (ratio of AUC_Cpep to AUC_gluc divided by HOMA-IR) was similar between the groups at baseline (median 54.1 vs. 51.3, p = 0.62) but after IIT was significantly higher in the responders (109.3 vs. 57.4, p = 0.009). At baseline, the strongest predictors of the change in beta-cell function were glucose levels between 180 and 240 min (all r = −0.5, p = 0.005) and incremental AUC_Cpep from 120 to 180 min (all r ≥ 0.66, p ≤ 0.0001), both reflecting late-phase insulin secretion.
Conclusions: The clinical response to short-term IIT is variable, consistent with the heterogeneity of T2DM. However, preserved late-phase insulin secretion may identify those patients who can benefit from this intervention with improved beta-cell function.     

Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes

To examine the role of intramyocellular lipid (IMCL) accumulation as well as circulating cytokines, branched-chain amino acids and acylcarnitines in the pathogenesis of muscle insulin resistance in healthy, young, lean insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured these factors in plasma and used (1)H magnetic resonance spectroscopy to assess IMCL content and hyperinsulinemic-euglycemic clamps using [6,6-(2)H(2)] glucose to assess rates of insulin-stimulated peripheral glucose metabolism before and after weight reduction. Seven lean (body mass index < 25 kg/m(2)), young, sedentary IR offspring were studied before and after weight stabilization following a hypocaloric (1,200 Kcal) diet for ～9 wks. This diet resulted in an average weight loss of 4.1 ± 0.6 kg (P < 0.0005), which was associated with an ～30% reduction of IMCL from 1.1 ± 0.2% to 0.8 ± 0.1% (P = 0.045) and an ～30% improvement in insulin-stimulated muscle glucose uptake [3.7 ± 0.3 vs. 4.8 ± 0.1 mg/(kg-min), P = 0.01]. This marked improvement in insulin-stimulated peripheral insulin responsiveness occurred independently of changes in plasma concentrations of TNF-α, IL-6, total adiponectin, C-reactive protein, acylcarnitines, and branched-chain amino acids. In conclusion, these data support the hypothesis that IMCL accumulation plays an important role in causing muscle insulin resistance in young, lean IR offspring, and that both are reversible with modest weight loss.     

Leptin levels in patients with type 1 diabetes receiving intensive insulin therapy compared with those in patients receiving conventional insulin therapy

Several reports suggest that insulin may have a role in the regulation of serum leptin levels, and this is related to the fact that serum leptin levels generally indicate the amount of body fat. Studies show that leptin levels are low in newly diagnosed patients with Type-1 diabetes (T1 DM) and increase after institution of insulin therapy. This study was designed to test whether serum leptin levels are higher in patients receiving intensive insulin therapy (IIT) compared to conventional insulin therapy (CIT). Young patients with T1 DM were studied, 23 on IIT and 23 on CIT. The patients were matched for age (19+/-3 and 20+/-5 yr, respectively), duration of diabetes (8+/-5 and 10+/-6 yr, respectively) and BMI (24+/-4 and 23+/-3 kg/m2, respectively). Leptin levels were higher in IIT compared to CIT (13+/-12 vs 7+/-7 ng/ml, respectively, p<0.05). The results of this study demonstrate that patients on IIT have higher leptin levels than patients on CIT. This increase in leptin level in IIT patients is independent of changes in bw and is probably due to the stimulatory effect of insulin on leptin production.     

强化胰岛素治疗在重型颅脑损伤中的临床应用价值探讨

目的：探讨强化胰岛素治疗（intensive insulin therapy,IIT）在重型颅脑损伤（severe traumatic brain injury,sTBI）中的临床应用价值。方法对200例sTBI患者（GCS评分3～8分）,入院后随机分为IIT组100例及常规胰岛素治疗（conventional insulin treatment ,CIT）组100例。 IIT组血糖（blood glucose,BG）控制在3.9～6.1 mmol／L,CIT组血糖控制在8.3～10.1 mmol／L。患者入院后即开始采用持续静脉泵入胰岛素对血糖进行控制,记录两组患者平均血糖水平、胰岛素用量、低血糖发生率,于伤后6个月时根据GOS评估法判断疗效（分为良好、中残、重残、植物生存和死亡）。结果治疗期IIT组BG低于CIT组（ P＜0.01）,低BG发生率、单位时间胰岛素用量均高于CIT组（ P＜0.05或P＜0.01）。伤后6个月,两组在良好、中残、重残、植物生存和死亡例数比较差异无统计学意义（ P＞0.05）。结论强化胰岛素治疗并不能改善sTBI的预后,且增加了低BG发生率,血糖控制在8.3～10.1 mmol／L是比较理想的水平。     

胰岛素强化治疗对2型糖尿病患者静息能量消耗的影响

目的观察胰岛素强化治疗对2型糖尿病（T2DM）患者静息能量消耗（REE）的影响。方法对26例T2DM患者经胰岛素强化治疗前后的『临床生化指标、炎症因子及REE进行比较分析。结果胰岛素强化治疗能显著降低REE,用体重（wt）校正后REE／Wt下降约10．4％（P=0．006）。多元回归分析提示REE与FPG、高敏C反应蛋白（hsDRP）、白介素6（IL-6）正相关（P〈0．05）。结论胰岛素强化治疗可降低T2DM患者的REE,REE的降低与血糖下降及炎症反应的改善相关。     

Physical exercise and pancreatic islets: Acute and chronic actions on insulin secretion

Diabetes mellitus (DM) is a great public health problem, which attacks part of the world population, being characterized by an imbalance in body glucose homeostasis. Physical exercise is pointed as a protective agent and is also recommended to people with DM. As pancreatic islets present an important role in glucose homeostasis, we aim to study the role of physical exercise (chronic adaptations and acute responses) in pancreatic islets functionality in Wistar male rats. First, animals were divided into two groups: sedentary (S) and aerobic trained (T). At the end of 8 weeks, half of them (S and T) were submitted to an acute exercise session (exercise until exhaustion), being subdivided as acute sedentary (AS) and acute trained (AT). After the experimental period, periepididymal, retroperitoneal and subcutaneous fat pads, blood, soleus muscle and pancreatic islets were collected and prepared for further analysis. From the pancreatic islets, total insulin content, insulin secretion stimulated by glucose, leucine, arginine and carbachol were analyzed. Our results pointed that body adiposity and glucose homeostasis improved with chronic physical exercise. In addition, total insulin content was reduced in group AT, insulin secretion stimulated by glucose was reduced in trained groups (T and AT) and insulin secretion stimulated by carbachol was increased in group AT. There were no significant differences in insulin secretion stimulated by arginine and leucine. We identified a possible modulating action on insulin secretion, probably related to the association of chronic adaptation with an acute response on cholinergic activity in pancreatic islets.     

Moderate-intensity endurance exercise prevents short-term starvation-induced intramyocellular lipid accumulation but not insulin resistance

Exercise has the potential to alleviate the resistance to insulin-mediated glucose uptake precipitated by elevated circulating free fatty acids (FFAs) in conditions such as obesity, lipid infusion, and starvation. In this study, 6 lean healthy men underwent two 3-day periods of starvation with either no exercise or daily endurance exercise (80 min d⁻¹ at 50% maximal rate of oxygen consumption) and a 3-day mixed diet without exercise. Insulin sensitivity was determined by intravenous glucose tolerance test, and intramyocellular lipid (IMCL) concentration was measured by ¹H magnetic resonance spectroscopy. In both starvation conditions, fasting plasma FFAs were significantly elevated, whereas plasma glucose and whole-body insulin sensitivity were significantly reduced. Vastus lateralis IMCL to water ratio was significantly elevated after starvation without exercise compared with that after starvation with exercise or that after mixed diet. Intramyocellular lipid to water ratio was not different between starvation with exercise and mixed diet. In healthy lean men, exercise during starvation prevents the accumulation of IMCL yet does not affect the starvation-induced changes in FFAs and insulin sensitivity. Unlike during lipid infusion or obesity-induced insulin resistance, exercise cannot overcome the reduction in insulin action caused by starvation. We propose that carbohydrate availability is a key modulator of the combined effects of exercise and circulating FFAs on insulin sensitivity.     

Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of beta-cell function with oral antidiabetic medications: a pilot study with sitagliptin

Aim: Studies evaluating the effects of oral antidiabetic drugs (OADs) on beta‐cell function in type 2 diabetes mellitus (T2DM) are confounded by an inability to establish the actual baseline degree of beta‐cell dysfunction, independent of the deleterious effects of hyperglycaemia (glucotoxicity). Because intensive insulin therapy (IIT) can induce normoglycaemia, we reasoned that short‐term IIT could enable evaluation of the beta‐cell protective capacity of OADs, free from confounding hyperglycaemia. We applied this strategy to assess the effect of sitagliptin on beta‐cell function. Methods: In this pilot study, 37 patients with T2DM of 6.0 + 6.4 years duration and A1c 7.0 + 0.8% on 0–2 OADs were switched to 4–8 weeks of IIT consisting of basal detemir and premeal insulin aspart. Subjects achieving fasting glucose <7.0 mmol/l 1 day after completing IIT (n = 21) were then randomized to metformin with either sitagliptin (n = 10) or placebo (n = 11). Subjects were followed for 48 weeks, with serial assessment of beta‐cell function [ratio of AUC_Cpep to AUC_gluc over Homeostasis Model Assessment of Insulin Resistance (HOMA‐IR) (AUC_Cpep/gluc/HOMA‐IR)] on 4‐h meal tests. Results: During the study, fasting glucagon‐like‐peptide‐1 was higher (p = 0.003) and A1c lower in the sitagliptin arm (p = 0.016). Nevertheless, although beta‐cell function improved during the IIT phase, it declined similarly in both arms over time (p = 0.61). By study end, AUC_Cpep/gluc/HOMA‐IR was not significantly different between the placebo and sitagliptin arms (median 71.2 vs 80.4; p = 0.36). Conclusions: Pretreatment IIT can provide a useful strategy for evaluating the beta‐cell protective capacity of diabetes interventions. In this pilot study, improved A1c with sitagliptin could not be attributed to a significant effect on preservation of beta‐cell function.     

Non-oxidative glucose disposal is reduced in type 2 diabetes, but can be restored by aerobic exercise

Whole-body glucose utilization consists of mitochondrial glucose oxidation and non-oxidative glycogen synthesis. We examined whether reduction of both non-oxidative glucose disposal and glucose oxidation contributes to insulin resistance in type 2 diabetes. We also examined the effects of exercise on these two components. Whole-body glucose disposal rate (GDR, mg/kg/min) was evaluated in 37 type 2 diabetic (T2DM) and 17 non-diabetic (non-DM) subjects as the mean of glucose infusion rate during steady state in the euglycaemic–hyperinsulinaemic clamp study. Glucose oxidation rates were assessed by indirect calorimetry, and non-oxidative GDR was calculated by subtracting glucose oxidation rate from GDR. Intramyocellular lipid (IMCL) content of the soleus muscle was measured using ¹H-magnetic resonance spectroscopy. In 10 T2DM subjects, the changes in oxidative and non-oxidative glucose disposal during clamp were examined after 3-month exercise intervention. GDR (2.93 ± 1.55 vs. 4.55 ± 1.83, p = 0.001) and non-oxidative GDR (1.45 ± 1.52 vs. 3.01 ± 1.87, p = 0.002) were significantly lower in T2DM than in non-DM subjects. Glucose oxidation rate was comparable in the two groups, and inversely correlated with IMCL (n = 15, r =−0.565, p = 0.028). GDR (2.28 ± 1.67 to 4.63 ± 2.42, p = 0.021) and non-oxidative GDR (0.72 ± 1.27 to 2.26 ± 1.91, p = 0.047) were increased after exercise intervention, although the change in glucose oxidation rate was not significant. In summary, reduction of non-oxidative glucose disposal may contribute to decreased whole-body glucose utilization. In addition, exercise improves insulin resistance mainly by increasing non-oxidative glucose disposal in type 2 diabetes.     

Association of parental cardiovascular risk factors with offspring type 1 diabetes mellitus insulin sensitivity

AimThis study aimed to determine whether the insulin resistance (IR) and lipid profiles in Type 1 Diabetes (T1D) offspring are associated with IR and other cardiovascular risk factors in their parents.MethodsThis study included 99 T1D patients (19.6 ± 4.0 yrs.), 85 mothers and 60 fathers. Parents' IR was assessed by HOMA-IR, and the insulin sensitivity in T1D patients was assessed by the estimated Glucose Disposal Rate (eGDR).ResultsThe eGDR in the T1D offspring was negatively related to age (p = 0.023), weight (p = 0.004), LDL (p = 0.026), and microalbuminuria (p = 0.019). Maternal Type 2 Diabetes (p < 0.001) and HOMA-IR (p = 0.029) were negatively related to eGDR in their T1D offspring. The maternal HOMA-IR and the proband's eGDR were positively (p = 0.012) and negatively (p = 0.042) associated with the birth weight of the T1D offspring, respectively. We didn't find an association with the fathers' profiles.ConclusionsIn a cohort of offspring with T1D the insulin sensitivity was related to the IR, lipid profile, and the presence of T2D only in their mothers. Precocious screening and treatment of these risk factors beyond glycemic control will benefit T1D with this background.     

Does insulin resistance in type 2 diabetes alter vitamin D status?

AimsData on changes of vitamin D due to insulin resistance are conflicting. We assessed vitamin D concentrations and parameters of glycemia and mineral homeostasis in patients with insulin resistant type 2 diabetes and in matched normal controls.MethodsSixty-nine patients with type 2 diabetes and 60 matched normal control subjects were studied. After an overnight fast, blood was collected for measuring the parameters of glycemia (glucose, insulin and HbA1c), mineral profile (corrected calcium, phosphate and alkaline phosphatase), total 25(OH) vitamin D and parathyroid hormone (PTH) levels.ResultsPatients had significantly elevated fasting glucose (P = 0.0001), insulin (P = 0.0003) and HbA1c (P = 0.0005) than the controls had. They had significantly raised calculated insulin resistance compared with control subjects (P = 0.0001). Patients and controls had similar levels of serum corrected calcium and ALP, whereas serum phosphate was significantly lower in the patients compared with controls (P = 0.001).Patients and controls had similar levels of 25(OH)D, but the levels of 25(OH)D in both were in the deficiency range. Intact PTH was similar in the patients and controls. Levels of 25(OH)D did not demonstrate any relation with fasting insulin, insulin resistance, or HbA1c, but correlated negatively with intact PTH (r = ?0.4, P = 0.02).ConclusionThis study demonstrated prevalent vitamin D deficiency in insulin resistant type 2 diabetic and normal subjects. Insulin resistance did not influence the status of vitamin D.     

Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle

Aims/hypothesis  TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. Methods  Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic–hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. Results  Insulin stimulation increased glucose uptake in both legs, with greater effects (~80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho–AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14–3–3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. Conclusion/interpretation  We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.     

The effect of exercise training on glucose tolerance and skeletal muscle triacylglycerol content in rats fed with a high-fat diet

The aim of the present study was to evaluate the effect of exercise training on glucose tolerance and glycogen and triacylglycerol (TG) content in different types of skeletal muscles and in the liver of rats fed with a high-fat diet. From 8 to 11 weeks of age male Wistar rats were fed with isocaloric standard (control) or high-fat diet (HFD--59% calories as fat) and were additionally assigned to a sedentary or trained group (4 weeks of training on a treadmill). An intravenous glucose tolerance test (IVGTT) with the determination of basal and post load insulin was performed before the final tissue sampling. HFD rats developed marked hyperinsulinemia. Exercise training improved glucose tolerance and insulin response in the control group only (AUC for glucose in control sedentary vs control trained, p<0.05; AUC for insulin: control sedentary vs control trained, p<0.005). Liver glycogen was significantly lower in the HFD group (p<0.05 vs control sedentary) and did not increase after exercise training. Muscle and liver TG content was markedly higher in the HFD group in comparison to control (p<0.0001 in all cases). Exercise training increased TG content in the control group in all examined tissues except white gastrocnemius (p<0.001 in all cases compared to sedentary controls), and did not affect tissue TG in the HFD group. After exercise training there was still markedly higher tissue TG content in the HFD group vs control (p<0.0001 in all cases). We conclude that beneficial metabolic effects of training are impaired in high-fat fed rats and that training does not completely reverse metabolic disturbances in this group of animals.