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1.
2.

OBJECTIVE

We investigated whether palmitoleate, which prevents insulin resistance in mice, predicts insulin sensitivity in humans.

RESEARCH DESIGN AND METHODS

The fasting fatty acid pattern in the plasma free fatty acid (FFA) fraction was determined in 100 subjects at increased risk for type 2 diabetes. Insulin sensitivity was estimated during an oral glucose tolerance test (OGTT) at baseline and after 9 months of lifestyle intervention and measured during the euglycemic-hyperinsulinemic clamp (n = 79).

RESULTS

Circulating palmitoleate (OGTT:F ratio = 8.2, P = 0.005; clamp:F ratio = 7.8, P = 0.007) but not total FFAs (OGTT:F ratio = 0.6, P = 0.42; clamp:F ratio = 0.7, P = 0.40) correlated positively with insulin sensitivity, independently of age, sex, and adiposity. High baseline palmitoleate predicted a larger increase in insulin sensitivity. For 1-SD increase in palmitoleate, the odds ratio for being in the highest versus the lowest tertile of adjusted change in insulin sensitivity was 2.35 (95% CI 1.16–5.35).

CONCLUSIONS

Circulating palmitoleate strongly and independently predicts insulin sensitivity, suggesting that it plays an important role in the pathophysiology of insulin resistance in humans.Free fatty acids (FFAs) are considered to link obesity with insulin resistance and type 2 diabetes (1,2). Mechanisms include intracellular accumulation of lipotoxic metabolites, such as long-chain fatty acyl-CoA, ceramides, and diacylglycerol, which interfere with insulin signaling (2) and signaling via membrane toll-like receptor 4 (3). However, a significant relationship between total FFA levels and insulin resistance is not found in all studies (46).Most recently, the fatty acid palmitoleate (C16:1n7) was found to increase insulin action in skeletal muscle and to prevent hepatosteatosis in mice, thus representing a link between adipose tissue and systemic metabolism (7). In the present study, we investigated whether palmitoleate may also be a determinant of insulin sensitivity in humans.  相似文献   

3.

OBJECTIVE

To determine if glucose and C-peptide values obtained as part of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study could be used to estimate insulin sensitivity during late pregnancy.

RESEARCH DESIGN AND METHODS

A total of 78 women enrolled in the HAPO study were recruited for this ancillary study. Venous plasma samples were drawn after an 8- to 10-h fast (time 0) and at 30, 60, 90, and 120 min after a 75-g glucose challenge, which was performed at 24–32 weeks'' gestation. Samples were analyzed for plasma glucose, insulin, and C-peptide. Insulin sensitivity was estimated using the established Matsuda and DeFronzo insulin sensitivity index for oral glucose tolerance tests (ISOGTT). Insulin sensitivity was also calculated from two other commonly used indexes of insulin sensitivity (that for homeostasis model assessment [ISHOMA] and that for quantitative insulin sensitivity check index [ISQUICKI]). A new insulin sensitivity index was calculated using the glucose and C-peptide concentrations at 0 and 60 min to derive ISHOMA C-pep, ISQUICKI C-pep, and ISOGTT C-pep. These indexes were then correlated with insulin sensitivity estimated from the ISOGTT.

RESULTS

The strongest correlation with the ISOGTT was obtained for ISOGTT C-pep (r = 0.792, P < 0.001). Further, the correlations of ISHOMA C-pep and ISQUICKI C-pep with ISOGTT were also significant (r = 0.676, P < 0.001 and r = 0.707, P < 0.001, respectively).

CONCLUSIONS

These data suggest that calculated ISOGTT C-pep is an excellent predictor of insulin sensitivity in pregnancy and can be used to estimate insulin sensitivity in over 25,000 women participating in the HAPO study.Gestational diabetes mellitus (GDM) is a common metabolic disorder in developed countries occurring in 2–10% of pregnancies (1). GDM is associated with an increased risk of maternal and perinatal complications such as preeclampsia, macrosomia, shoulder dystocia, and neonatal hypoglycemia. Furthermore, the offspring of GDM pregnancies have an increased risk of obesity and type 2 diabetes in later life (2,3). In a recent study, Crowther et al. (4) reported that treatment of GDM in the form of dietary advice, blood glucose monitoring, and insulin therapy as required for glycemic control reduces the rate of serious perinatal complications. Although the risks associated with GDM are well recognized, there has been no general agreement about which glucose criteria should be used for diagnosis of GDM based primarily on maternal perinatal and neonatal outcomes.The recently completed Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was a prospective observational study during which >25,000 pregnant women in 10 different countries were recruited to determine the levels of glycemia, less severe than diabetes, associated with risks of large for gestational age, clinical neonatal hypoglycemia, cord-blood C-peptide, and primary cesarean delivery (5) as well as neonatal adiposity (6). The results confirm that there is a strong continuous association between maternal glucose concentrations below those currently used to diagnose GDM and adverse perinatal outcomes.Normal human pregnancy is characterized by a significant decrease in insulin sensitivity (7). Furthermore, women developing GDM in addition to an inadequate insulin response have decreased insulin sensitivity compared with women with normal glucose tolerance (8). In many of these studies, insulin sensitivity has been estimated using a euglycemic-hyperinsulinemic clamp, which is considered the gold standard method. However, the clamp is a complicated, high-cost, and labor-intensive procedure and is not suitable for large studies.Various investigators have validated indexes of insulin sensitivity derived from an oral glucose tolerance test (ISOGTT) (9) or fasting glucose and insulin levels (that for homeostasis model assessment [ISHOMA] and that for quantitative insulin sensitivity check index [ISQUICKI]) (10,11): in all these studies, only nonpregnant adults were evaluated. However, we recently reported a study of normal glucose tolerant and GDM pregnant women, comparing different indexes of insulin sensitivity derived from OGTTs with hyperinsulinemic-euglycemic clamps throughout pregnancy (12). We concluded that during pregnancy, the ISOGTT was the index that best correlated with insulin sensitivity when compared with the euglycemic-hyperinsulinemic clamp (r = 0.86, P < 0.001). Hence, the purpose of this study was to investigate if insulin sensitivity could be reasonably estimated using glucose and C-peptide measures obtained during a 75-g OGTT in HAPO study subjects.  相似文献   

4.

OBJECTIVE

To examine sex-specific black/white differences in lipoprotein profile and the role of visceral adiposity and to assess the relationship between insulin sensitivity and lipoprotein profiles in each group.

RESEARCH DESIGN AND METHODS

Fasting lipoprotein particle size and concentration and visceral adipose tissue (VAT) were determined in 226 children (117 black, 101 male) aged 8 to <18 years. The relationship between lipoproteins and insulin sensitivity was evaluated in a subset of 194 children (100 black, 88 male) who underwent a hyperinsulinemic-euglycemic clamp.

RESULTS

Black male children had smaller VLDL and black female children had larger HDL size than their white counterparts. Overall, blacks had larger LDL size with no sex-specific race differences. After adjusting for VAT and sex, only VLDL size and concentrations remained significantly favorable in blacks. Analysis of lipoprotein particle size and concentration across insulin sensitivity quartiles revealed that in both racial groups, the most insulin-resistant children had higher concentrations of small dense LDL, small HDL, and large VLDL and smaller LDL and HDL sizes than their more insulin-sensitive counterparts.

CONCLUSIONS

The previously reported favorable lipoprotein profiles in black versus white children is partly due to race differences in VAT. In both groups, however, the most insulin-resistant youths have a high-risk atherogenic profile of small dense LDL, small HDL, and large VLDL, akin to the atherogenic lipoprotein pattern in adults with coronary artery disease.Type 2 diabetes and insulin resistance in children are associated with dyslipidemia (1,2), characterized by elevated triglycerides and LDL cholesterol and low concentrations of HDL cholesterol (13). In addition to traditional lipid profiles, evidence suggests that insulin resistance and type 2 diabetes are associated with changes in lipoprotein particle size and subclass concentration (2,4). These are important to assess, as traditional lipid measurements only partially predict disease risk (5). Recently, the SEARCH for Diabetes in Youth study (2) reported that 36% of youth with type 2 diabetes and 62% of those with poorly controlled diabetes had small dense LDL. Similarly, low proportions of large and high proportions of small HDL particles are found in children with type 2 diabetes and overweight, insulin-resistant children (4). However, whereas some investigators reported associations between LDL (6,7), HDL (8), and VLDL (6) particle size and fasting insulin, others did not (9). High triglyceride and low HDL cholesterol concentrations together with small, dense LDL in children with type 2 diabetes and insulin resistance are similar to the atherogenic lipoprotein phenotype in adults with coronary artery disease (10,11).Black children, despite being insulin resistant and hyperinsulinemic (12,13) compared with their white counterparts, have favorable lipid concentrations including lower LDL and triglyceride and higher HDL concentrations (3,14,15), larger HDL and LDL and smaller VLDL particles, and favorable lipoprotein subclass concentrations (6,8). Why black children have favorable lipoprotein profiles despite insulin resistance is not clear. One explanation could be lower visceral adiposity in black than in white children despite similar overall adiposity (15). In black adults insulin resistance is not a good marker of triglyceride or HDL cholesterol concentrations or lipoprotein particle size (16). Thus, the relationship between in vivo insulin sensitivity and lipoprotein profiles in black and white children needs to be examined if at-risk children are to be identified for early treatments to improve lipoprotein profiles and if those treatments are to be pertinent in children of different ethnicity.In the present study, therefore, we determined lipoprotein particle size and subclass concentrations in black and white children and measured in vivo insulin sensitivity to test the following hypotheses: 1) the favorable lipoprotein phenotype in black children is probably due to lower visceral adipose tissue (VAT) than in whites and 2) the relationship between insulin sensitivity and lipoprotein profile is similar between black and white children.  相似文献   

5.

OBJECTIVE

We aimed to examine insulin clearance, a compensatory mechanism to changes in insulin sensitivity, across sex, race/ethnicity populations, and varying states of glucose tolerance.

RESEARCH DESIGN AND METHODS

We measured insulin sensitivity index (SI), acute insulin response (AIR), and metabolic clearance rate of insulin (MCRI) by the frequently sampled intravenous glucose tolerance test in 1,295 participants in the Insulin Resistance Atherosclerosis Study.

RESULTS

MCRI was positively related to SI and negatively to AIR and adiposity across sex, race/ethnicity populations, and varying states of glucose tolerance, adiposity, and family history of diabetes. Differences in MCRI by race/ethnicity (lower in African Americans and Hispanics compared with non-Hispanic whites) and glucose tolerance were largely explained by differences in adiposity, SI, and AIR.

CONCLUSIONS

Insulin sensitivity, insulin secretion, and adiposity are correlates of insulin clearance and appear to explain differences in insulin clearance by race/ethnicity and glucose tolerance status.Reduced insulin clearance has been demonstrated in experimental models of insulin resistance (1) and conditions associated with insulin resistance (25). Insulin clearance partially explains the variability of fasting insulin independently of the effect of insulin resistance, insulin secretion, adiposity, and plasma glucose (6). In response to their higher insulin resistance, minority populations have lower insulin clearance than non-Hispanic whites (4,5,7). In these studies, however, results were not adjusted for insulin resistance. Therefore, we aimed to examine insulin clearance across sex, race/ethnicity populations, and varying states of glucose tolerance in the Insulin Resistance Atherosclerosis Study (IRAS) (8).  相似文献   

6.

OBJECTIVE

The Indian Diabetes Prevention Programme-1 (IDPP-1) showed that lifestyle modification (LSM) and metformin were effective for primary prevention of diabetes in subjects with impaired glucose tolerance (IGT). Among subjects followed up for 3 years (n = 502), risk reductions versus those for the control group were 28.5, 26.4, and 28.2% in LSM, metformin (MET), and LSM plus MET groups, respectively. In this analysis, the roles of changes in secretion and action of insulin in improving the outcome were studied.

RESEARCH DESIGN AND METHODS

For this analysis, 437 subjects (93 subjects with normoglycemia [NGT], 150 subjects with IGT, and 194 subjects with diabetes) were included. Measurements of anthropometry, plasma glucose, and plasma insulin at baseline and at follow-up were available for all of them. Indexes of insulin resistance (homeostasis model assessment of insulin resistance) and β-cell function (insulinogenic index [ΔI/G]: 30-min fasting insulin divided by 30-min glucose) were also analyzed in relation to the outcome.

RESULTS

Subjects with IGT showed a deterioration in β-cell function with time. Individuals with higher insulin resistance and/or low β-cell function at baseline had poor outcome on follow-up. In relation to no abnormalities, the highest incidence of diabetes occurred when both abnormalities coexisted (54.9 vs. 33.7%, χ2 = 7.53, P = 0.006). Individuals having abnormal insulin resistance (41.1%) or abnormal ΔI/G (51.2%, χ2 = 4.87, P = 0.027 vs. no abnormalities) had lower incidence. Normal β-cell function with improved insulin sensitivity facilitated reversal to NGT, whereas deterioration in both resulted in diabetes. The beneficial changes were better with intervention than in the control group. Intervention groups had higher rates of NGT and lower rates of diabetes.

CONCLUSIONS

In the IDPP-1 subjects, beneficial outcomes occurred because of improved insulin action and sensitivity caused by the intervention strategies.Primary prevention studies in diabetes have been done in subjects with a high risk for diabetes, such as those with impaired glucose tolerance (IGT) (16) or with a history of gestational diabetes mellitus (7). Lifestyle modification (LSM) (15) and/or pharmacological agents such as metformin (MET) (1,5) and glitazones (6) have been shown to be effective in reducing the rate of conversion of IGT to diabetes in different ethnic groups. The benefits are seen in association with weight reduction in the obese population (1,2) or without significant weight changes in relatively nonobese population (3,5). The mechanisms that result in the beneficial changes are associated with two important pathophysiological components, namely impaired secretion and impaired action of insulin.The Indian Diabetes Prevention Programme-1 (IDPP-1) had shown that moderate, but consistent, LSM or use of MET reduced the risk of deterioration of IGT to diabetes by 28% in relation to that in a control group who had no intervention in a 3-year follow-up period (5). Combining LSM with MET showed no added benefit.IGT, an intermediate state in the natural history of type 2 diabetes, is characterized by a worsening in insulin resistance and insulin secretion (8). Asian Indians have higher rates of insulin resistance than Europeans and other white populations despite being relatively nonobese (9,10).The chief pathophysiological components of type 2 diabetes, namely impaired secretion and action of insulin are detectable many years before the diagnosis of clinical diabetes (11). A combined occurrence of both defects due to gradual deterioration, eventually results in diabetes. This analysis was done to identify the changes in insulin secretion and insulin action that produced the improved outcome with the primary prevention strategies in the IDPP-1 cohort.  相似文献   

7.

OBJECTIVE

The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS).

RESEARCH DESIGN AND METHODS

In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up.

RESULTS

Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25–3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex.

CONCLUSIONS

Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.Type 2 diabetes (T2D) is associated with depression (1,2). Plausible mechanisms underlying this association include the depressogenic effect of the treatment and management of T2D (36) and of the influence of the T2D diagnosis itself because it can be viewed as a stressful life event (7,8). Recently, the hypothesis that the link between diabetes and depression results from a direct biological impact of diabetes-related biological changes has raised particular interest. More specifically, it has been proposed that hyperglycemia and hyperinsulinemia may alter hypothalamic-pituitary-adrenal (HPA) axis function, which, in turn, increases the risk of depressive symptoms (DepS) (9,10).To date, the results from observational studies investigating the association between fasting glucose level and depression are mixed. Some investigations found that impaired fasting glucose (11) and high glycated hemoglobin (12) are associated with increased DepS, but others failed to observe this association (4,1315) or suggested that the association varies by sex (16,17). Similarly, associations between hyperinsulinemia, insulin resistance, and depression showed conflicting results with findings from six studies showing a positive association between insulin resistance and DepS (1723), two reporting a null effect (24,25), and one suggesting that insulin resistance is inversely associated with DepS (26). Methodological limitations, such as cross-sectional study design and small sample size, may have contributed to these inconsistencies. Furthermore, the possibility of a nonlinear relationship between levels of fasting glucose (7) or insulin and DepS may explain these inconsistencies.To dissect the effect of T2D diagnosis and treatment from the influences of biomarkers, it is crucial to examine associations prospectively between insulin and glucose levels and DepS and controlling for T2D status. It is also crucial to take into account the wide range of factors that could act as confounders. For example, the associations between levels of glucose and insulin and DepS may be explained by common causes such as obesity, low socioeconomic status, or stroke.In the present large-scale longitudinal study, we examined whether measures of glucose and insulin were prospectively associated with new-onset DepS over 5 years of follow-up. To minimize the depressogenic effects of T2D diagnosis and treatment, analyses took into account T2D status at study baseline and repeated in a subgroup of nondiabetic participants. We tested the strength of the findings by controlling for a wide range of potential confounders and mediators, including sociodemographic characteristics; health behaviors; inflammatory markers; cortisol; and health factors, such as cardiovascular and cerebrovascular diseases.  相似文献   

8.

OBJECTIVE

The study objective was to assess the relationship between β-cell function and HbA1c.

RESEARCH DESIGN AND METHODS

A total of 522 Mexican American subjects participated in this study. Each subject received a 75-g oral glucose tolerance test (OGTT) after a 10- to 12-h overnight fast. Insulin sensitivity was assessed with the Matsuda index. Insulin secretory rate was quantitated from deconvolution of the plasma C-peptide concentration. β-Cell function was assessed with the insulin secretion/insulin resistance (IS/IR) (disposition) index and was related to the level of HbA1c.

RESULTS

At HbA1c levels <5.5%, both the Matsuda index of insulin sensitivity and IS/IR index were constant. However, as the HbA1c increased >5.5%, there was a precipitous decrease in both the Matsuda index and the IS/IR index. Subjects with HbA1c = 6.0–6.4% had a 44 and 74% decrease in the Matsuda index and the IS/IR index, respectively, compared with subjects with HbA1c <5.5% (P < 0.01 for both indices). Subjects with normal glucose tolerance and HbA1c <5.7% had β-cell function comparable to that of subjects with normal glucose tolerance with HbA1c = 5.7–6.4%. However, subjects with impaired fasting glucose or impaired glucose tolerance had a marked decrease in β-cell function independent of their HbA1c level.

CONCLUSIONS

The results of the current study demonstrate that in Mexican Americans, as HbA1c increases >6.0%, both insulin sensitivity and β-cell function decrease markedly. Performing an OGTT is pivotal for accurate identification of subjects with impaired β-cell function.In 1997, the American Diabetes Association (ADA) revised its criteria for the diagnosis of type 2 diabetes and determined that subjects with fasting plasma glucose (FPG) >126 mg/dL and 2-h plasma glucose ≥200 mg/dL are considered to have type 2 diabetes (1). These cut points were chosen on the basis of the increased incidence of diabetic retinopathy rather than on the presence of metabolic abnormalities (i.e., insulin resistance and β-cell dysfunction) that are responsible for type 2 diabetes (1).Impaired β-cell function is the principal factor responsible for the development and progression of type 2 diabetes (2). In addition to β-cell dysfunction, subjects with type 2 diabetes manifest severe insulin resistance in skeletal muscle, liver, and adipocytes (36). Insulin resistance is the earliest metabolic abnormality detected in subjects destined to develop type 2 diabetes. In response to insulin resistance, the β-cell appropriately increases insulin secretion and normal glucose tolerance (NGT) is maintained. However, when β-cell failure ensues, glucose intolerance develops. Initially, this is manifest as impaired glucose tolerance (IGT) and subsequently as overt diabetes (1). Thus, impaired β-cell function is an essential condition in the development of type 2 diabetes (1).Although normal β-cell function is pivotal to the maintenance of NGT, β-cell failure develops long before hyperglycemia becomes evident. Recent studies have demonstrated that the decrease in β-cell function begins in the range considered to be well within NGT according to the 1997 ADA criteria (710). Studies that have related β-cell function to FPG (7,8) and 2-h plasma glucose (9,10) concentrations reported that β-cell function progressively declined with the increase in both FPG and 2-h plasma glucose from the low normal range to the high normal range, to the impaired glucose tolerant and diabetic ranges. These results indicate that the decrease in β-cell function, which is the primary factor responsible for the deterioration of glucose tolerance, is a continuum with no threshold above which β-cell dysfunction develops.ADA recently changed the diagnostic criteria for type 2 diabetes to include individuals with HbA1c ≥6.5%; high-risk individuals are defined as having an HbA1c = 5.7–6.4% (11,12). No data are available relating the HbA1c to β-cell function. Therefore, the aim of the current study was to examine the relationship between β-cell function and HbA1c.  相似文献   

9.

OBJECTIVE

Although insulin resistance (IR) may underlie associations between depressive symptoms and diabetes, previous findings have been contradictory. We examined whether depressive symptoms associate with IR and insulin secretion, and, additionally, whether antidepressant medication use may modulate such associations.

RESEARCH DESIGN AND METHODS

A total of 4,419 individuals underwent an oral glucose tolerance test (OGTT). Participants with previously or newly diagnosed diabetes are excluded from this sample. The homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR) were calculated. Depressive symptoms and antidepressant medication use were self-reported.

RESULTS

After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-min insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations.

CONCLUSIONS

Depressive symptoms are associated with IR but not with changes in insulin response when corrected for IR in individuals without previously or newly diagnosed diabetes.Depressive symptoms are associated with type 2 diabetes (1) and the metabolic syndrome (2,3), and insulin resistance (IR) is thought to be the underlying factor. However, previous findings have been conflicting because depressive symptoms have been reported to be associated with both higher IR (4) and lower IR (5), whereas some studies have reported null associations (6,7). We examined associations of depressive symptoms with IR and insulin secretion in individuals without diabetes. We also tested if antidepressant medications modulated these associations, as one study suggests that antidepressant medication, such as the use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, may improve insulin sensitivity (8). Yet, one study reported that antidepressant medications and insulin sensitivity are not related (9), whereas some studies have reported that antidepressant medications may decrease insulin sensitivity and increase the risk of type 2 diabetes (10,11).  相似文献   

10.

OBJECTIVE

Sleep disorders and subjective sleep complaints have been associated with increased risk of type 2 diabetes. The evidence with respect to insulin resistance (IR) and insulin secretion in individuals without type 2 diabetes has been scarce and elusive. We examined if subjective sleep complaints and their co-occurrence were associated with IR and insulin secretion in adult women and men without diabetes.

RESEARCH DESIGN AND METHODS

Women (n = 442) and men (n = 354) 18–75 years of age without type 2 diabetes underwent an oral glucose tolerance test (OGTT), with insulin and glucose measured at fasting and at 30 and 120 min. Complaints related to sleep apnea, insomnia, and daytime sleepiness were self-rated with the Basic Nordic Sleep Questionnaire.

RESULTS

In comparison with individuals with no or minor sleep complaints, those with more frequent complaints of sleep apnea, insomnia, and daytime sleepiness were more insulin resistant, as evidenced by higher fasting insulin concentrations and insulin and glucose responses to OGTT, and more frequently had high homeostasis model assessment of IR and low insulin sensitivity index values. The likelihood of being insulin resistant increased significantly and linearly according to the accumulation of co-occurring sleep complaints. These associations changed only a little when adjusted for mediating and confounding factors and for depressive symptoms. Sleep complaints were not associated with indices of deficiency in insulin secretion.

CONCLUSIONS

Subjective sleep complaints were associated with IR. The likelihood of being insulin resistant increased according to accumulation of co-occurring sleep complaints. Sleep complaints were not associated with deficiency in insulin secretion.In several cross-sectional and prospective studies, sleep apnea, sleep disordered breathing, habitual snoring, insomnia, difficulties in initiating and maintaining sleep, and daytime sleepiness have been associated with the prevalence and the incidence of type 2 diabetes (16). Although these findings suggest that sleep disorders and subjective sleep complaints may carry an increased risk for type 2 diabetes, the evidence with respect to insulin resistance (IR) and insulin secretion, two major features of type 2 diabetes, in individuals without type 2 diabetes has been scarce and elusive.In individuals without a history of or concurrently diagnosed type 2 diabetes, polysomnography-based sleep disordered breathing was associated with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) (2), a higher degree of IR (7,8), and a decreased degree of insulin sensitivity and pancreatic β-cell function during a frequently sampled intravenous glucose tolerance test (9). However, subjective complaints of sleep apnea, habitual snoring, and daytime sleepiness were not associated with IFG, IGT, and IR (10). Finally, a recent study has reported that subjective complaints of frequent snoring were not associated with fasting insulin, glucose, and IR, whereas insomnia, a combined measure of actigraphy-based sleep latency and fragmentation, and subjective complaints were associated with lower fasting insulin values and a lower likelihood of being insulin resistant (4).We studied whether subjective complaints of sleep apnea (habitual snoring and sleep disordered breathing), insomnia (difficulties in initiating and/or maintaining sleep), and daytime sleepiness were associated with IR and insulin secretion in a population-based sample of 18–75-year-old Finnish women and men without a history of or concurrently diagnosed type 2 diabetes. Our study contributes to previous studies in two ways. First, we tested if the degree of glycemia and IR increased according to accumulation of subjective sleep complaints that often co-occur together (11,12). Second, we tested if symptoms of depression accounted for the associations. The latter was seen as relevant since sleep complaints may indicate the presence of depression (13), and symptoms of depression have been linked with the prevalence and the incidence of type 2 diabetes (14,15), and with IR in populations without type 2 diabetes (16).  相似文献   

11.

OBJECTIVE

Age-associated insulin resistance may underlie the higher prevalence of type 2 diabetes in older adults. We examined a corollary hypothesis that obesity and level of chronic physical inactivity are the true causes for this ostensible effect of aging on insulin resistance.

RESEARCH DESIGN AND METHODS

We compared insulin sensitivity in 7 younger endurance-trained athletes, 12 older athletes, 11 younger normal-weight subjects, 10 older normal-weight subjects, 15 younger obese subjects, and 15 older obese subjects using a glucose clamp. The nonathletes were sedentary.

RESULTS

Insulin sensitivity was not different in younger endurance-trained athletes versus older athletes, in younger normal-weight subjects versus older normal-weight subjects, or in younger obese subjects versus older obese subjects. Regardless of age, athletes were more insulin sensitive than normal-weight sedentary subjects, who in turn were more insulin sensitive than obese subjects.

CONCLUSIONS

Insulin resistance may not be characteristic of aging but rather associated with obesity and physical inactivity.There is a widespread assertion that aging leads to insulin resistance (13), which is in turn fundamental to the etiology and higher prevalence of type 2 diabetes in older adults (46). The evidence supporting the concept of age-associated insulin resistance, however, is contradicted by reports demonstrating that insulin resistance may not be associated with aging per se but rather with lifestyle patterns linked with aging, such as a reduced physical activity (7) and obesity (8). Thus, it is not clear whether insulin resistance is characteristic of aging or, alternatively, whether obesity and/or physical inactivity underlie this “aging” effect. The purpose of this study was to help detangle the effects of aging, obesity, and chronic exercise on insulin resistance by comparing younger and older subjects matched for level of obesity and chronic physical activity.  相似文献   

12.

OBJECTIVE

Coffee consumption has been associated with lower risk of type 2 diabetes. We evaluated the acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance.

RESEARCH DESIGN AND METHODS

We conducted a randomized crossover trial of the effects of 12 g decaffeinated coffee, 1 g chlorogenic acid, 500 mg trigonelline, and placebo (1 g mannitol) on glucose and insulin concentrations during a 2-h oral glucose tolerance test (OGTT) in 15 overweight men.

RESULTS

Chlorogenic acid and trigonelline ingestion significantly reduced glucose (−0.7 mmol/l, P = 0.007, and −0.5 mmol/l, P = 0.024, respectively) and insulin (−73 pmol/l, P = 0.038, and −117 pmol/l, P = 0.007) concentrations 15 min following an OGTT compared with placebo. None of the treatments affected insulin or glucose area under the curve values during the OGTT compared with placebo.

CONCLUSIONS

Chlorogenic acid and trigonelline reduced early glucose and insulin responses during an OGTT.In prospective cohort studies, higher coffee consumption has been associated with a lower risk of type 2 diabetes (1,2). Associations have been similar for caffeinated and decaffeinated coffee (1,35), suggesting that coffee components other than caffeine have beneficial effects on glucose homeostasis. Coffee is a major source of the phenolic compound chlorogenic acid (6) and the vitamin B3 precursor trigonelline (7), which have been shown to reduce blood glucose concentrations in animal studies (58). This is the first study to investigate the acute effects of chlorogenic acid and trigonelline on glucose tolerance in humans.  相似文献   

13.

OBJECTIVE

Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.

RESEARCH DESIGN AND METHODS

Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m2 per min) combined with 3-[3H] glucose infusion.

RESULTS

Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).

CONCLUSIONS

Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.Fibroblast growth factors (FGFs) represent a group of peptides that regulate diverse biological functions, including cell differentiation, cell growth, and angiogenesis (1,2). Recently, a subfamily of FGFs that interact with nuclear receptors has been identified that plays an important role in liver, bone, and adipose tissue metabolism (3,4). This subfamily contains FGF-19, which regulates energy expenditure (5,6); FGF-23, which regulates phosphate metabolism and excretion (7); and the recently described FGF-21, which regulates glucose homeostasis (8,9).FGF-21 is a novel protein that has been implicated in the regulation of lipid and glucose metabolism under fasting and ketotic conditions (9,10). In murine models, FGF-21 was reported to be expressed predominantly in liver (11), but its expression has also been reported in adipose tissue and pancreatic β-cells (12). In a primate model of diabetes, Kharitonenkov et al. (9) reported a reduction in plasma glucose, insulin, triglycerides, LDL cholesterol, and HDL cholesterol levels following 6 weeks of recombinant FGF-21 administration. In diet-induced obese mice, FGF-21 reversed hepatic steatosis and improved insulin sensitivity (13). In adipose tissue, FGF-21 was shown to increase glucose uptake (9). Based on these observations, FGF-21 has been proposed as a potential therapeutic agent for type 2 diabetes in humans (14). However, few studies in humans have examined the relationship between FGF-21 and glucose/lipid metabolism. Chen et al. (15) reported that patients with newly diagnosed type 2 diabetes had significantly higher plasma FGF-21 concentrations than nondiabetic control subjects, and FGF-21 negatively correlated with fasting plasma glucose. More recently, Zhang et al. (16) found that FGF-21 concentrations are elevated in obese nondiabetic individuals compared with lean healthy control subjects and that the circulating levels correlated positively with adiposity and fasting insulin and negatively with HDL cholesterol. Conversely, in patients with anorexia nervosa, plasma FGF-21 concentrations are decreased and increased following weight gain (17). In the present study, we examined the relationship between plasma FGF-21 concentrations and direct measurements of peripheral and hepatic insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.  相似文献   

14.

OBJECTIVE

Disposition index (DI) and glucose effectiveness (SG) are risk factors for diabetes. However, the effect of DI and SG on future diabetes has not been examined in large epidemiological studies using direct measures.

RESEARCH DESIGN AND METHODS

Insulin sensitivity index (SI), acute insulin response (AIR), and SG were measured in 826 participants (aged 40–69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as SI × AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.

RESULTS

The area under the receiver operating characteristic curve of a model with SI and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and SG, conversion to diabetes was predicted by both SG (odds ratio × 1 SD, 0.61 [0.47–0.80]) and DI (0.68 [0.54–0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of SG and DI to incident diabetes.

CONCLUSIONS

The predictive power of DI is comparable to that of its components, SI and AIR. SG and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.Both insulin sensitivity and first-phase insulin secretion are independent determinants of conversion to diabetes in different ethnic groups and varying states of glucose tolerance, family history of diabetes, and obesity (1). First-phase insulin secretion compensates for the worsening of insulin sensitivity (2). In studies using direct methods, such as the frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis, this relationship is hyperbolic (2) and similar across glucose tolerance categories (3). Known as the disposition index (DI), the product of measures of insulin sensitivity and first-phase insulin secretion, it has been shown to predict conversion to diabetes (46). The evidence, however, comes from studies that have enrolled relatively few participants or targeted persons from a single ethnic group. Since direct methods have demanding technical requirements, the product of measures of insulin sensitivity and insulin secretion derived from the oral glucose tolerance test has attracted interest. This product has been shown to have a modest correlation with minimal model–derived DI, to decrease as glucose tolerance status deteriorates, and to predict the development of diabetes independent of other risk factors including fasting and 2-h glucose concentrations (7,8). It includes the incretin effect and therefore may not always follow the hyperbolic law (79). The hyperbolic paradigm of the minimal model–derived DI has also been criticized (10). Furthermore, its predictive power has not been tested for large epidemiological studies.In addition to the insulin-dependent component of glucose tolerance (or DI), the insulin-independent component (glucose effectiveness [SG]) has already been explored in mice (11) and humans (12). SG is the capacity of glucose to enhance its own cellular uptake and to suppress endogenous glucose production. Although reduced in individuals with impaired glucose tolerance (IGT) and diabetes (4,13), SG contributes to glucose tolerance even in conditions of significant insulin resistance, including diabetes (13). Reduced SG has also been described in healthy individuals following the infusion of cortisol or glucagon, individuals in states of very low caloric intake, women with polycystic ovary syndrome, and the elderly (1315). Contrary to the insulin sensitivity index (SI), SG may not be influenced by exercise (16) or weight loss interventions (17). In relatively small studies, SG has been shown to predict future diabetes (4,5,18), but its contribution to the development of diabetes remains largely unknown.Since the hyperbolic paradigm has not been tested in large epidemiological studies, our first objective was to analyze the risk of future diabetes associated with minimal model-derived DI relative to its components, SI, and acute insulin response (AIR). The second objective was to assess the relative contribution of the insulin-independent component of glucose tolerance, SG, to the development of diabetes. To meet these aims, we used data from the Insulin Resistance Atherosclerosis Study (IRAS), a multicenter observational epidemiological study of different ethnic groups and varying states of glucose tolerance (19).  相似文献   

15.

OBJECTIVE

To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).

RESULTS

At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.

CONCLUSIONS

In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.Treatment of hyperglycemia in patients with type 2 diabetes remains a challenge, particularly in those who require insulin as the disease progresses (1,2). Various combinations of insulin with oral antidiabetic agents (OADs) have been investigated (28). Often, these combination therapies become less effective in controlling hyperglycemia over time, particularly as a result of weight gain and worsening insulin resistance as well as progressive failure of insulin secretion.Hypoglycemia, weight gain, and subsequent increased insulin resistance are significant factors that limit optimal titration and effectiveness of insulin (2). Weight gain with insulin therapy, used alone or with OADs (79), is in part a consequence of reducing glucosuria (10,11). Among commonly used OADs, thiazolidinediones (TZDs) and sulfonylureas intrinsically contribute to weight gain, whereas metformin causes weight loss and dipeptidyl peptidase-4 inhibitors are weight neutral. Overall, there is a need for novel agents that can be safely administered to help achieve glycemic targets without increasing the risks of weight gain or hypoglycemia.A novel approach to treating hyperglycemia targets receptors for renal glucose reabsorption (12). Agents that selectively block sodium-glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, inhibit glucose reabsorption and induce its elimination through urinary excretion (13). Preclinical models have shown that SGLT2 inhibition lowers blood glucose independently of insulin (1417). Dapagliflozin, a highly selective inhibitor of SGLT2, has demonstrated efficacy, alone or in combination with metformin, in reducing hyperglycemia in patients with type 2 diabetes (18,19) but has not been tested in patients requiring insulin. This study was designed to determine whether dapagliflozin is effective in lowering blood glucose in patients with type 2 diabetes who have not responded adequately to insulin combined with oral therapies that act through insulin-dependent mechanisms.  相似文献   

16.

OBJECTIVE

Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.

RESEARCH DESIGN AND METHODS

We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).

RESULTS

A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6–41) and 11% (−3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4–43) and 4% (−12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.

CONCLUSIONS

Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.Insulin resistance is an established risk factor for cardiovascular and noncardiovascular diseases. Insulin resistance is associated with increased risk of cardiovascular disease events in diverse community-based populations, whether it is measured directly (1,2), estimated using fasting insulin concentration (e.g., homeostasis model assessment [HOMA]) (39), or calculated using dynamic testing (e.g., oral glucose tolerance test [OGTT]) (9,10). Insulin resistance is also associated with increased risk of noncardiovascular diseases, including cancer (2,11). Insulin resistance promotes endothelial dysfunction, oxidative stress, and inflammation and is closely linked with other cardiovascular risk factors (obesity, hypertension, and dyslipidemia) as part of metabolic syndrome (12). Through these mechanisms, insulin resistance may be causally related to adverse clinical outcomes.Kidney function may play an important role in the relationship of insulin resistance with adverse health outcomes. Impaired kidney function is known to be linked with insulin resistance (13). The causal nature of this relationship is not well defined: impaired kidney function may promote insulin resistance through retained uremic toxins, acidosis, and active vitamin D deficiency; insulin resistance may contribute to the development of impaired kidney function by damaging glomerular endothelial and epithelial cells; and/or shared risk factors (e.g., obesity or genetic predisposition) may underlie both insulin resistance and impaired kidney function (1418). Lower glomerular filtration rate (GFR), even within the normal range (≥60 mL/min/1.73 m2), is strongly associated with increased risks of cardiovascular disease and death, particularly among older adults (19,20). It is therefore possible that impaired kidney function confounds or mediates known associations of insulin resistance with cardiovascular and noncardiovascular diseases.We explored whether impaired kidney function confounds or mediates the relationship of insulin resistance with mortality. We chose all-cause mortality as our primary outcome to reflect the pleiotropic effects of insulin resistance. We studied this relationship in the Cardiovascular Health Study (CHS), a community-based population of older adults, because insulin resistance and impaired kidney function are each known strong risk factors for adverse health outcomes among older people (1,19,20). In addition, CHS obtained baseline data ascertaining insulin resistance in both fasting and dynamic states; measured baseline serum cystatin C, which may better discriminate differences in kidney function and its associated health risks in the normal range (2023); and followed participants for >15 years. These data allow a comprehensive evaluation of the relationships of interest.  相似文献   

17.

OBJECTIVE

Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.

RESEARCH DESIGN AND METHODS

We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.

RESULTS

In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.

CONCLUSIONS

In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).Individuals with impaired glucose tolerance (IGT) are at high risk for diabetes; ∼50% of all IGT subjects progress to diabetes during their lifetime, with annual diabetes conversion rates that vary between 3 and 11% (1,2). Therefore, it is important to identify these individuals at high risk and to institute preventive therapy, be it lifestyle modification (3,4) or pharmacologic therapy, to prevent the development of microvascular and macrovascular complications (511).In ACT NOW, 602 IGT subjects at high risk were randomly assigned to receive therapy with placebo or pioglitazone, in addition to advice about diet and exercise (7,12). During a mean follow-up period of 2.4 years, subjects in the placebo and pioglitazone groups experienced conversion to diabetes at the rates of 7.6 and 2.1%, respectively (hazard ratio 0.28; P < 0.00001). All subjects in ACT NOW underwent baseline phenotypic, anthropometric, and clinical measurements. An oral glucose tolerance test (OGTT) measuring plasma glucose, free fatty acid (FFA), insulin, and C-peptide (CP) concentrations was performed to provide indices of glucose tolerance, insulin secretion, β-cell function, and insulin sensitivity at baseline (1217). In the current study, we describe those variables that are independent predictors of type 2 diabetes mellitus (T2DM) in IGT subjects treated with placebo in ACT NOW, and we describe a multivariate model that is highly predictive of the eventual development of diabetes. In the predictive model, we used variables that are routinely obtained by practicing physicians, as well as physiologic variables derived from the OGTT.  相似文献   

18.

OBJECTIVE

To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS

After preliminary testing, 11 male patients (24 ± 2 years, HbA1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg−1 BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO2peak. At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg−1 BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system.

RESULTS

All glycemic responses were similar across conditions up to 60 min postexercise. After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs. Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L−1], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions.

CONCLUSIONS

A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia.Patients with type 1 diabetes are encouraged to engage in regular exercise as part of a healthy lifestyle (1,2). However, engaging in exercise is not without its difficulties (1). Defective glucose regulation presents a significant challenge in preventing hypoglycemia during, and particularly after, exercise (3,4). Exercise-induced hypoglycemia is both a frequent (5) and dangerous occurrence (6) and remains a major obstacle to patients who wish to engage in exercise (7).Much of the literature has focused on providing strategies to help combat hypoglycemia during, and early after, exercise (817), with investigations focusing on altering exercise modality (14,18), carbohydrate consumption (12,16,17), and reductions to pre-exercise, rapid-acting insulin dose (1012,17,19). Prior to moderate-intensity, continuous, aerobic exercise, it is recommended that patients should reduce their prandial rapid-acting insulin dose by ∼75% to prevent hypoglycemia during exercise (1012). However, despite best preserving blood glucose, it has been shown that this strategy is not fully protective against postexercise hypoglycemia (11,12). This has, in part, been attributed to iatrogenic causes (11), whereby patients administer their usual doses of rapid-acting insulin in a heightened insulin-sensitive state, potentially leading to unexpected falls in blood glucose and, consequently, hypoglycemia (11).A potential strategy to help minimize the risk of developing hypoglycemia after exercise could be to reduce the dose of rapid-acting insulin administered with the postexercise meal (20). Exercise increases the sensitivity of the body to insulin for many hours after exercise (3) and patients could be faced with a window of particularly high sensitivity around the postexercise meal, whereby greater rates of glucose uptake could occur to supplement the high metabolic priority of replenishing muscle glycogen (21). Thus, the meal consumed after exercise is important. With this in mind, it would be intuitive to reduce the amount of insulin administered with the meal consumed at this time; this may preserve glycemia and prevent postexercise hypoglycemia. Conversely, severe reductions in rapid-acting insulin dose may incur prolonged postexercise hyperglycemia, even more so if the pre-exercise dose is also reduced. However, there is a lack of data to confirm or refute these hypotheses. In addition, it would be prudent to examine the extent to which rapid-acting insulin dose adjustments may help combat late falls in glycemia after exercise, considering type 1 diabetic patients are susceptible to late-onset, postexercise hypoglycemia (3), suggested to be due to a biphasic response in glucose uptake occurring early and also late after exercise (22). Therefore, the aim of this study was to examine the acute and 24-h postexercise glycemic responses to reducing the postexercise rapid-acting insulin dose, when using the recommended pre-exercise insulin reductions, in type 1 diabetic patients.  相似文献   

19.

OBJECTIVE

To determine whether an electronic order template for basal-bolus insulin ordering improves mean blood glucose in hospitalized general medical patients with hyperglycemia and type 2 diabetes.

RESEARCH DESIGN AND METHODS

We randomly assigned internal medicine resident teams on acute general medical floors to the use of an electronic insulin order template or usual insulin ordering. We measured diabetes care parameters for 1 month on all patients with type 2 diabetes and blood glucose <60 mg/dl or >180 mg/dl treated by these physicians.

RESULTS

Intervention group patients (n = 65) had mean glucose of 195 ± 66 mg/dl. Control group patients (n = 63) had mean glucose of 224 ± 57 mg/dl (P = 0.004). In the intervention group, there was no increase in hypoglycemia.

CONCLUSIONS

Access to a computer insulin order template was associated with improved mean glucose levels without increasing hypoglycemia in patients with type 2 diabetes.Physiological, basal-bolus insulin prescribing is safe, effective (1), and the standard of care in hospitalized patients with type 2 diabetes and hyperglycemia (2). Yet only about half of such patients are prescribed basal insulin in the hospital (3). Order templates to support basal-bolus insulin prescribing (usually as part of a comprehensive inpatient diabetes quality improvement program) have been effective in improving glycemia in observational trials (48). Randomized trials have shown more modest effects (9,10). Knowledge of appropriate insulin ordering is a barrier to ordering basal-bolus insulin among inpatient providers (1113).We tested the hypothesis that giving internal medicine residents access to an electronic insulin order template would be more effective than usual insulin ordering in lowering mean blood glucose in medical inpatients with type 2 diabetes.  相似文献   

20.

OBJECTIVE

Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by an subcutaneous glucose sensor have encountered delays and variability of insulin absorption. We tested closed-loop intraperitoneal insulin infusion from an implanted pump driven by an subcutaneous glucose sensor via a proportional-integral-derivative (PID) algorithm.

RESEARCH DESIGN AND METHODS

Two-day closed-loop therapy (except for a 15-min premeal manual bolus) was compared with a 1-day control phase with intraperitoneal open-loop insulin delivery, according to randomized order, in a hospital setting in eight type 1 diabetic patients treated by implanted pumps. The percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was the primary end point.

RESULTS

During the closed-loop phases, the mean ± SEM percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was significantly higher (39.1 ± 4.5 vs. 27.7 ± 6.2%, P = 0.05), and overall dispersion of blood glucose values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4–6.6 mmol/l range (46.3 ± 5.3 vs. 28.6 ± 7.4, P = 0.025) and lower mean blood glucose levels (6.9 ± 0.3 vs. 7.9 ± 0.6 mmol/l, P = 0.036). Time spent with blood glucose <3.3 mmol/l was low and similar for both investigational phases.

CONCLUSIONS

Our results demonstrate the feasibility of intraperitoneal insulin delivery for an artificial β-cell and support the need for further study. Moreover, according to a semiautomated mode, the features of the premeal bolus in terms of timing and amount warrant further research.In patients with type 1 diabetes, the near-normal glucose control required to prevent long-term complications (1,2) remains difficult to achieve (3). Indeed, the incidence of hypoglycemia increases when glucose control approaches normal glucose levels (4). For this reason the development of an “artificial pancreas” has been a goal for >30 years (5,6).An artificial β-cell requires three elements: a continuous insulin delivery device, a continuous glucose monitoring system, and a control algorithm linking insulin delivery to glucose measurements (3,7,8). The recent development of better performing continuous glucose sensors renewed the potential feasibility of closed-loop insulin delivery (911). Short-term initiatives in the clinical research setting were reported in recent years but showed some limitations (1214). Key limiting factors were, first, delays in the modulation of insulin action related to subcutaneous infusion and, second, time lags in glucose detection due to either the placement of the sensors in the interstitial compartment of subcutaneous tissue or the internal structure of implanted intravenous sensors (15). To reduce glucose deviations at mealtimes, a hybrid option of closed-loop insulin delivery includes a manual priming bolus (16).Reported benefits of intraperitoneal insulin infusion from implantable pumps include fast insulin action and low basal plasma insulin levels, resulting in tight glucose control and a low incidence of hypoglycemic events (17). The feasibility of automated closed-loop insulin delivery from implantable pumps has been demonstrated in clinical trials performed with the Long-Term Sensor System, which coupled these devices with an intravenous glucose sensor (18).Our approach to optimize closed-loop glucose control includes the use of closer to physiological intraperitoneal insulin delivery, subcutaneous glucose sensing, and a proportional-integral-derivative (PID) algorithm with a manual premeal bolus, resulting in a hybrid PID (HyPID) system. The objective of this study was to test the feasibility of such an approach. We investigated patients in the same controlled hospital setting while testing the HyPID system and when following their usual self-management. This approach marks a difference from the previously reported closed-loop trials, which considered home-use periods for comparison with in-clinic closed-loop studies (13,16).  相似文献   

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