Insulin sensitivity factor in type 2 diabetes genetic,m. tibialis anterior funktion,s online tap 235 - Test Out

The insulin-like growth factor (IGF) system, acting in concert with other hormone axes, is important in normal metabolism. Changing relationships between fasting IGFBP-1 and insulin concentrations, and bioavailable (free) IGF-I in tissues in peripheral and hepatic insulin resistance.
AcknowledgmentsThe authors acknowledge the support of the Berth von Kantzows Foundation (to Kerstin Hall). American Journal of Physiology - Endocrinology and Metabolism Published 4 February 2005 Vol.
AbstractTo investigate early secretory defects in prediabetes, we evaluated ?-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects.
Obesity is a disease that can be defined as an excess of body fat that is enough to impair health, welfare and quality of life.
Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and the prevalence of these disorders is rising globally at epidemic rates. In recent years, a growing body of evidence has linked inflammation to the development of insulin resistance.
According to a University of Texas study, Crazy Ants may become the dominant invasive ant species displacing Fire Ants in the near future. Scientists have successfully placed tiny synthetic motors in live human cells through nanotechnology. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH) secretion, while total IGF-I levels are relatively unchanged due to increased hepatic GH sensitivity. IntroductionThroughout evolution the insulin-like growth factors (IGFs), their IGF-binding proteins (IGFBPs) and receptors have had central roles in growth, metabolism and reproduction [1].
IGFBPsIn humans there are six IGFBP genes encoding a family of highly conserved proteins that have high affinity binding for the IGFs [11]. Impaired Glucose Tolerance and Type 2 DiabetesFasting IGFBP-1 is a good predictive marker of abnormal glucose homeostasis, with low values predicting the development of impaired fasting glucose, impaired glucose tolerance and type 2 diabetes 8–17 years later [16,17,69,70].
?-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions.
Being overweight, which is also unhealthy for anyone, does not necessarily mean that the person has too much fat. In recent years, chronic low-grade inflammation has emerged as an important contributor to the development of insulin resistance. In insulin resistance, the hormone insulin is less effective in promoting glucose uptake from the bloodstream into other tissues.
Jerrold Olefsky and colleagues from the University of California in San Diego investigated the role of G protein-coupled receptor 21 (GPR21) in insulin resistance and energy homeostasis. IGF-binding protein (IGFBP)-1 levels are suppressed in relation to the increase in insulin levels in obesity and low levels predict the development of type 2 diabetes several years later. There is evidence that the IGF system has an important pathophysiological role across the spectrum of obesity, insulin resistance and type 2 diabetes mellitus, and therefore represents a potential therapeutic target.
Two of these, IGFBP-3 and IGFBP-5, when bound to IGF-I or IGF-II, can bind to a third protein, the acid-labile subunit (ALS).
In women who go on develop diabetes 8 years later, IGFBP-1 concentrations are low relative to insulin levels, perhaps due to a novel inhibitor of IGFBP-1. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 ± 6 vs. An overweight person may be so because of extra muscles, heavier bones, or extra water in his system. Obesity is a major factor that contributes to insulin resistance, which can eventually lead to type 2 diabetes. The group compared mice without the gene encoding GPR21 to healthy control mice under normal and high-fat diet conditions.
Visceral adiposity and hepatic steatosis, along with a chronic inflammation, contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated. The purpose of this review is to present a short summary of that evidence.Articles included were retrieved through PubMed using the MeSH terms “insulin-like growth factor” or “IGFBP” and identified by a manual search for English-language, full-text papers that related to obesity, insulin resistance and diabetes mellitus for the period 2009 to April 2014. ALS and IGF-I are growth hormone dependent and the high molecular mass ternary complex, since it is retained in the circulation, accounts for stable IGF-I concentrations in the face of pulsatile GH secretion. In both men and women, at the time of diagnosis of type 2 diabetes, fasting IGFBP-1 may rise in relation to insulin, which may be in part due to hepatic insulin resistance (Figure 2).
Previous studies have shown that proinflammatory molecules found in fat tissue decreases sensitivity of tissues to insulin.
They discovered that mice lacking GPR21 had enhanced insulin sensitivity and increased energy expenditure independent of diet.
The IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target. In addition one of the author’s own database of IGF and IGFBP references prior to 2009 was searched using the terms obesity, insulin resistance and diabetes.
Unbound or “free” IGFs (fIGFs) and IGFs in binary complexes have short half-lives in the circulation, measured in minutes to hours [12]. Impaired IGFBP-1 suppression in response to an oral glucose load is also a predictor, and may indicate hepatic insulin resistance; however it is not a better marker than the fasting concentrations [17,71]. This result was attributed to the reduced migration of inflammatory cells to the liver and fat tissue in the absence GPR21.
Total IGF measurements in single blood samples therefore underestimate this dynamic IGF turnover and fail to reflect tissue IGF production, which contributes to activity at the cellular level. Low IGFBP-2 and higher IGFBP-3 concentrations are also associated with incident diabetes in middle-aged women [70].Low IGF-I concentrations have been shown to predict later glucose intolerance and type 2 diabetes in some studies [72] and not others [16,17,69]. Under normal diet, absence of GPR21 in the hypothalamus caused a modest decrease in body weight. Determination of fIGF-I concentrations in interstitial fluid, for example, reveals concentrations that are higher than fIGF-I in plasma [13]. Free IGF-I concentrations are associated with incident diabetes in women with insulin levels above, and IGFBP-1 levels below, the median [70].Poorly controlled type 2 diabetes is associated with an increase in IGFBP-3 glycation, which increases affinity for IGF-I, as well as additional sialylation that has the converse effect, to decrease IGF-I affinity [73]. This is the first study to demonstrate the negative impact of GPR21 on inflammation and insulin sensitivity.
Although human studies were the primary focus, animal models that provide unique insights are also included.An understanding of the role of the IGF system in obesity, insulin resistance and diabetes requires an in depth knowledge of its role in normal metabolism.

There are also a number of IGFBP proteases that are tissue-specific and reduce or abolish IGF-binding affinity, thus adding further complexity to the system.It has long been realised that IGFBP-1 has an endocrine role in metabolism [14]. Their findings suggest that GPR21 inhibition may improve insulin resistance and enhance energy expenditure, making GPR21 inhibitors promising treatments for diabetes.
This will be described first, after which the recent IGF literature in relation to obesity, insulin resistance and type 2 diabetes will be reviewed in the context of previous work.
IGFBP-1 is secreted primarily from hepatocytes where synthesis is inhibited by insulin and stimulated by multiple regulators including glucagon, oestrogen, glucocorticoids, and pro-inflammatory cytokines [15]. Levels of soluble IGF2R in the circulation are increased [6,75].There is evidence to suggest that the IGF system, through effects on cell growth, metabolism and survival, plays a pathophysiological role in the cardiovascular complications of diabetes mellitus [76,77]. Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Therefore circulating IGFBP-1 concentrations reflect the combination of the inhibitory effect of portal insulin, the degree of hepatic insulin sensitivity and the actions of various stimulators [16]. IGFBP-3 appears to have protective effects on retinal vasculature, and may be a therapeutic candidate in retinopathy [78]. Phosphorylated forms of IGFBP-1 acutely inhibit IGF effects on 3T3-L1 preadipocytes and adipocytes [18]. In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, ?-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a ?-cell defect in the amplifying pathway of insulin secretion.insulin secretioninsulin sensitivityglucose tolerancemathematical modelsnormotolerant first-degree relatives of type 2 diabetic subjects (FDR) are an interesting model for the identification of early abnormalities of glucose homeostasis, which may be crucial to understanding the development of glucose intolerance. Specific proteolysis of IGFBP-1 generates IGF-binding fragments with reduced IGF-II-stimulated glucose uptake in muscle [19].The IGFBP family has other metabolic roles through IGF-independent as well as IGF-dependent mechanisms.
It has been suggested that IGF2BP2 might interact with IGF-II mRNA to protect males with type 1 diabetes from diabetic nephropathy [80]. Although not all reports are in agreement, FDR subjects are frequently insulin resistant and exhibit ?-cell function abnormalities (8, 11, 20), in particular if the degree of insulin resistance is taken into account (2).
Studies in 3T3-L1 cells have demonstrated that IGFBP-3 inhibits adipogenic differentiation through direct interaction with PPAR-gamma [20] and IGFBP-2 expression in 3T3-L1 adipocytes is upregulated by insulin [21].
This concept has been more clearly established using intravenous tests (hyperglycemic clamp, intravenous glucose tolerance test), as the assessment of ?-cell function from an oral glucose load or mixed meal is complicated by the necessity to account for varying glucose levels. Studies in animal models show that IGFBP-3 knockout increases adiposity [22] and that IGFBP-3 also affects insulin secretion directly by IGF-independent as well as IGF-dependent mechanisms [23]. Thus the role that defective ?-cell function plays under normal living conditions is still undetermined.To assess ?-cell function in a state approximating free living, we have employed a 24-h, multiple-meal test with modeling analysis to quantify ?-cell function and the euglycemic insulin clamp to measure insulin sensitivity.
IGFBP-2 is also regulated by changes in nutritional status and it is speculated that IGFBP-1 and IGFBP-2, which both have Arg-Gly-Asp integrin recognition motifs, also modulate insulin sensitivity in an IGF independent manner [15,24]. It has been shown that IGFBP-2 is regulated by leptin and may mediate a portion of leptin’s antidiabetic effects [25].
Twenty-six FDR and 17 subjects without any history of type 2 diabetes (control subjects) participated in the study.
Subcutaneous adipose tissue from lean women has been shown to secrete predominantly IGF-II and IGFBP-4 [26] while in omental preadipocytes secrete PAPP-A, which cleaves IGFBP-4 [27]. FDR and control subjects were closely matched for sex, age, and body mass index (BMI), were healthy, and had a normal oral glucose tolerance test according to the American Diabetes Association criteria (Table 1).
Within the offspring group, six subjects had one parent with type 2 diabetes, 13 had one parent and two or more known second-degree relatives with type 2 diabetes, and seven had two FDR relatives (both parents).
The 26 relatives were from 22 unrelated families; if more than two offspring were available in a family, a maximum of two were randomly selected to participate. The control group was recruited by advertising from healthy volunteers without any family history of diabetes. Subjects in the control group were all unrelated, healthy, and of Caucasian origin and were taking no medication. Participants were asked to consume a weight-maintaining diet containing ?250 g of carbohydrate for 3 days before all examinations, and none was engaged in heavy physical exercise during this period. A questionnaire (18) dealing with daily physical activity patterns during work and leisure did not show differences between the two groups.
All subjects underwent a 24-h triple-meal test and a hyperinsulinemic euglycemic glucose clamp on separate days, as briefly described below. Role of the IGF System in ObesityObesity is associated with reduced spontaneous and stimulated GH secretion that is reversible with weight loss [29,30].
Written informed consent was obtained from all subjects, and the protocol was approved by the Ethics Committee of the County of Aarhus. GH deficient patients have central adiposity that is reduced by GH replacement, and it is therefore proposed that the suppressed GH level in obesity is in part responsible for a shift to relatively greater visceral adiposity [9]. Additional details on the subjects’ characteristics and experimental procedures can be found in Ref. Structural determinants for high-affinity binding of insulin-like growth factor ii to insulin receptor (IR)-A, the exon 11 minus isoform of the IR.
It may be a consequence of suppressed IGFBP-1 due to increased portal insulin concentrations in response to peripheral insulin resistance (Figure 1).
According to this hypothesis changes in IGFBP-1, by inversely regulating free IGF availability, alter the feedback inhibition of GH secretion. Consistent with this idea, IGFBP-1 levels are known to correlate inversely with insulin concentrations and measures of adiposity [16,17,32,33]. However, while it has been reported that fIGF-I levels are high in obesity [34], other studies show that fIGF-I is not increased [35] or may even decrease [36]. In an experimental setting, a two-week period of overeating was associated with increases in insulin, decreased IGFBP-1, increased fIGF-I and reduced GH [37]. Total energy intake was ?10 MJ for men and ?8 MJ for women (30% breakfast, 35% lunch, and 35% dinner). However most of the decline in GH concentrations occurred before the increase in fIGF-I in the circulation. Although this might suggest the process is independent of IGFBP-1, it is still possible that lower concentrations of IGFBP-1 in tissues has an effect on fIGF-I action at the cellular level. In a study of obese individuals before and after weight loss, GH secretion normalised while fIGF-I levels increased [29]. The insulin infusion rate was 1 mU·min?1·kg?1 (6 pmol·min?1·kg?1), and plasma glucose was clamped at ?5 mM. Differences in assay techniques for fIGF-I may also contribute to the differences observed in some of these studies.Recent work suggests that insulin may have a unique inhibitory effect on GH secretion.

Insulin-stimulated glucose uptake (M value) was calculated as the average glucose infusion rate between times 120 and 150 min, and was expressed in micromoles per minute per kilogram of lean body mass, as measured by bioelectric impedance. Plasma glucose, insulin, C-peptide, FFA, GIP, and GLP-1 concentrations were measured as previously reported (16).
It appears likely that sensitivity to insulin in obesity is preserved in some tissues where it plays a central role in the GH-IGF axis response, by inhibiting pituitary GH, increasing hepatic GH responsiveness and suppressing hepatic IGFBP-1 secretion [30,39].Obesity is associated with an increased IGF-I response to GH [39,40], and increased GH-binding protein levels [39], so that an increase in expression of GH receptor may explain lack of suppression of total IGF-I levels. The assay for GIP and GLP-1 available at the time of measurement allowed determination of total hormone concentration only.Modeling AnalysisThe ?-cell model used in the present study, describing the relationship between insulin secretion and glucose concentration, has been previously illustrated in detail (13, 14). Circulating total IGF-I concentrations in simple obesity are reported as low, normal or high [29]. Insulin secretion, S(t), consists of two components: The first component, Sg(t), represents the dependence of insulin secretion on absolute glucose concentration (G) at any time point and is characterized by a dose-response function, f(G), relating the two variables.
Some studies report an inverse relationship between total IGF-I concentrations and measures of adiposity, such as waist circumference corrected for height [32,41].
Characteristic parameters of the dose response are its mean slope in the 5–7 mM glucose range, denoted here as glucose sensitivity, and insulin secretion at a fixed glucose concentration of 5 mM (approximately the normal fasting level), ISR5. The dose response is modulated by a potentiation factor, P(t), which is a positive function of time, averaging 1 during the experiment: In the present context, the term potentiation refers to the fact that insulin secretion during the 24-h test can be higher or lower than that predicted by a simple dose-response model.
A large study of adults in which IGF-I levels were adjusted for age also documented a U-shaped relationship: the relationship with BMI was positive in normal weight and negative in obese individuals. In this sense, P(t) expresses a relative potentiation of insulin secretion, which encompasses physiological mechanisms that have a different origin and are known in the literature by different names.
BMI accounted for a small effect, just 1%, of the variance in IGF-I in normal weight subjects, and this increased to 7% in obese individuals [43].The relationship between IGF-II and obesity is even less certain. From these, estimated model parameters [the parameters of the dose response f(G) and the potentiation factor P(t); see Refs.
Low IGF-II concentrations have been shown to predict weight gain and obesity in adults with [46] and without [47] type 2 diabetes. The potentiation factor was found to be linearly correlated with plasma GIP concentration on a minute-by-minute basis (see results). In children low IGF-II levels have been documented in obesity, along with lower IGFBP-2 concentrations, particularly in those with insulin resistance and evidence of chronic inflammation (increased IL-6 and TNF-alpha) [48].Childhood obesity is now a global health problem and there is a growing body of evidence of the role of the IGF system. A GIP potentiation index was calculated as the slope of the individual regression lines.Statistical AnalysisAll data are presented as means ± SE.
In obese children there are strong inverse relationships between IGFBP-1 concentrations and insulin resistance, as well as the metabolic syndrome [49]. In a Hong Kong study higher IGF-I and IGFBP-3 concentrations were observed in obesity and in relation to cardiovascular risk markers in adolescence [50]. In contrast another study has shown decreased total IGFBP-3 in obese adolescents and increased circulating IGFBP-3 protease activity and IGFBP-3 fragments [51]. Multiple regression analysis was carried out using standard techniques.RESULTSTwenty-Four-Hour Concentration ProfilesFigure 1 shows the mean 24-h profiles of plasma glucose, insulin, and C-peptide concentrations. Since IGFBP-3 fragments have reduced affinity for IGFs and may have altered IGFBP-3 receptor binding, the impact of these changes on both IGF-dependent and IGF-independent metabolic effects should be considered in future work.
Mean 24-h glucose was slightly but significantly higher in FDR than in control subjects (Table 1). Tumors, IGF-2, and hypoglycemia: Insights from the clinic, the laboratory, and the historical archive.
Insulin-like growth factor (IGF)-binding proteins: Interactions with IGFs and intrinsic bioactivities. Plasma glucose, C-peptide, and insulin concentrations (means ± SE) during the 24-h test in normotolerant first-degree relatives of type 2 diabetic patients (FDR; solid circles and solid lines) and control subjects (open squares and broken lines).
Insulin secretion during the 24-h test in FDR (solid circles and solid lines) and control subjects (open squares and broken lines). ?-Cell function parameters and insulin sensitivity?-Cell Function ParametersThe model-derived ?-cell dose-response function is shown in Fig. 3, and the ?-cell function parameters ISR5, glucose sensitivity, and kd are given in Table 2. Model-derived ?-cell dose response in FDR (solid circles and solid lines) and control subjects (open squares and broken lines).
SE bars are shown at 1 mM glucose increments.The 24-h profiles of the potentiation factor are shown in Fig. Stimulation of potentiation during meals was less pronounced in FDR; in particular, the mean potentiation factor during the first 2 h of the test was 20% lower in FDR than in control subjects (Table 2). This difference in potentiation was also confirmed using an index that quantifies the average rise in potentiation factor during meals.
Because by assumption the 24-h mean potentiation factor is 1, in FDR subjects the lower meal potentiation peaks are accompanied by higher nocturnal and between-meal potentiation levels. IGF-dependent and IGF-independent actions of IGF-binding protein-1 and -2: Implications for metabolic homeostasis.
Insulin-like growth factor-binding protein-1 in the prediction and development of type 2 diabetes in middle-aged swedish men. Insulin-like growth factor-binding protein-1 and abdominal obesity in the development of type 2 diabetes in women.
IGF-binding protein-1 inhibits IGF effects on adipocyte function: Implications for insulin-like actions at the adipocyte. Specific cleavage of insulin-like growth factor-binding protein-1 by a novel protease activity. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. Human IGF binding protein-3 overexpression impairs glucose regulation in mice via an inhibition of insulin secretion.

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