Insulin sensitivity and glucose tolerance -
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Resources ADA Professional Membership ADA Member Directory Diabetes. X Twitter Facebook LinkedIn. This Feature Is Available To Subscribers Only Sign In or Create an Account. This is a blood test taken after an eight-hour overnight fast to measure blood glucose levels.
This type of blood glucose test is done over several stages. First, a fasting blood sample is taken to get a fasting glucose reading. Secondly, you are given a syrupy pure glucose solution to drink.
Finally, a healthcare practitioner will measure your blood glucose levels again two hours after drinking the solution.
This blood test gives an average of your blood glucose levels over two to three months. The recommended blood glucose levels for diagnosing diabetes and intermediate hyperglycemia prediabetes by the American Diabetes Association are as follows:. The treatment for glucose intolerance may differ depending on if you have been diagnosed with IFG, IGT, or type 2 diabetes.
Treatment includes lifestyle interventions, but in some cases, medication may be prescribed. The following lifestyle modifications are recommended from the research:.
Food such as ultra-processed foods and sugar-sweetened drinks are associated with an increased risk of type 2 diabetes. By comparison, consuming adequate protein from lean whole foods, non-starchy veggies, and high-fiber unrefined carbohydrates have been shown to reduce the risk of diabetes.
The CDC shows that exercise helps control your blood sugar levels. It also lowers your risk of heart disease and nerve damage. Body mass index is a measure of body fat based on height and weight that applies to adult men and women.
According to the American Diabetes Association , being overweight not only raises your risk for type 2 diabetes but also of heart disease and stroke.
Even a small amount of weight loss can make a big difference. Binge drinking and large quantities of alcohol can be harmful to many aspects of metabolic health. Too much alcohol may cause pancreatitis, which impairs the ability of the pancreas to secrete insulin.
This, in turn, can potentially increase risk for diabetes. The Food and Drug Administration FDA reports that smokers are 30 to 40 percent more likely to develop type 2 diabetes than nonsmokers. Medication may be prescribed to help lower blood sugar levels.
The most common medication prescribed is Metformin. Your doctor might also advise medication to control cholesterol or high blood pressure if these are additional problems that you have.
Using a CGM can help you monitor and understand your glucose levels throughout the day. This may allow you to gain insight into what diet and lifestyle factors impact your glucose levels.
Your body is unique and may respond differently to certain foods. Therefore, there is no way of knowing how each type of food impacts your glucose levels unless you are wearing a CGM and can observe what happens to your glucose levels in real time.
A CGM shows you how your glucose levels react to diet, exercise, medication, sleep, and stress. This allows you to develop a truly personalized nutrition plan and modify your lifestyle to reach optimal health. Wearing a CGM will give you deeper insight into your overall metabolic health and help you better understand what factors impact your glucose levels.
Several variations of the FSIVGTT have been published. One recently published study infused 0. The SI was calculated by a computer-based program.
Tolbutamide administration can also be used during FSIVGTT to augment endogenous insulin secretion and is particularly useful in women with diabetes. Continuous infusion of glucose with model assessment CIGMA : Like ITT, CIGMA requires fewer venipunctures and is less laborious than clamp techniques.
A constant IV glucose infusion is administered, and samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate SI. The results are reasonably compatible with clamp techniques; however, few laboratories have used CIGMA for insulin sensitivity testing in diabetic patients and there is no substantive data using the CIGMA technique in women with PCOS.
Oral glucose tolerance test OGTT : OGTT, a mainstay in the diagnosis of impaired glucose tolerance IGT and diabetes mellitus in pregnant and nonpregnant women, may be used to assess insulin sensitivity as well.
Because no IV access is needed, OGTT is better suited for assessment of large populations than the other techniques we outlined. A modified OGTT that uses a or g glucose load and measures glucose and insulin at various intervals over 2 to 4 hours has been used in clinical studies.
Like other minimal approaches to diagnosis, OGTT provides information on beta cell secretion and peripheral insulin action, and various mathematical equations have been used to provide an SI value. Insulin resistance has also been assessed qualitatively if one or more insulin values exceed an upper limit of normal at appropriate intervals.
Researchers have compared various methods for assessing insulin sensitivity in type 2 diabetics using the OGTT and found good correlations between AUCinsulin, insulin level at minutes I , and the steady state plasma glucose concentrations derived from a modified ITT.
As mentioned before, the search for uncomplicated and inexpensive quantitative tools to evaluate insulin sensitivity has led to development of fasting state homeostatic assessments.
These tests are based on fasting glucose and fasting insulin, and use straightforward mathematical calculations to assess insulin sensitivity and beta cell function. Several homeostatic approaches have been developed in recent years, each with its merits and deficiencies.
One of the weaknesses of these models is that they assume the relationship between glucose and insulin is linear when in fact it's parabolic. Fasting insulin I0 : Fasting serum insulin is an inexpensive assay, and does not require any mathematical calculations.
At least one researcher has advocated averaging two or three readings to account for day-to-day variability. Although I0 is less variable than other fasting procedures in normoglycemic patients, clinicians must still interpret results cautiously. Remember that insulin sensitivity is the ability of the hormone to reduce serum glucose.
If fasting glucose is high—for example, in a patient with impaired glucose tolerance—that may indicate a diminished effect from circulating insulin or in severe cases of insulin resistance, diminished quantity of the hormone. Hence I0 should not be used in glucose-intolerant or diabetic patients.
The ratio of glucose to insulin is easily calculated, with lower values depicting higher degrees of insulin resistance. Homeostatic model assessment HOMA : HOMA has been widely employed in clinical research to assess insulin sensitivity.
The constant should be replaced by The HOMA value correlates well with clamp techniques and has been frequently used to assess changes in insulin sensitivity after treatment. Quantitative insulin sensitivity check index QUICKI : Like HOMA, QUICKI can be applied to normoglycemic and hyperglycemic patients.
BMC Medicine volume 17Article glucosr Cite this anr. Metrics details. Insulin resistance IR is predictive Insulin sensitivity and glucose tolerance Anti-fungal nail treatments 2 snd and associated with Inuslin metabolic abnormalities in Insulin sensitivity and glucose tolerance conditions. However, limited data are available on how IR affects metabolic responses in a non-fasting setting, yet this is the state people are mostly exposed to during waking hours in the modern society. Here, we aim to comprehensively characterise the metabolic changes in response to an oral glucose test OGTT and assess the associations of these changes with IR.Kimberly P. Kinzig, Mary Ann Honors, Sara L. Low-carbohydrate, Insulin sensitivity and glucose tolerance diets KD are frequently implemented glucsoe efforts Metabolic rate and calorie restriction reduce or maintain body weight, toleranfe the metabolic effects of long-term exposure to this type of Insklin remain controversial.
This study toleance the responsivity to peripheral and golerance insulin, glucose tolerance, and meal-induced effects of Insuulin a KD in the rat.
After 8 wk of consuming chow or KD, caloric intake Insuljn peripheral or central insulin and insulin and Plant-based diet levels after a sehsitivity challenge were assessed.
In a separate group of rats, Magnesium for athletes and Inslin responses to either a low- or high-carbohydrate test meal were measured. Sebsitivity, rats maintained on KD qnd switched back to Nutritional strategies for improved sleep chow Insulin sensitivity and glucose tolerance, and insulin sensitivity and glucose tolerance were evaluated to determine whether the effects of Glucoes were reversible.
Maintenance on KD resulted in decreased sensitivity to peripheral insulin and Insulin sensitivity and glucose tolerance glucose tolerance. Furthermore, sensitvity of Carbs and exercise performance high-carbohydrate meal in rats that habitually consumed KD induced significantly greater insulin and glucose levels for an extended period of time, as compared with chow-fed controls.
Responsivity to central insulin was heightened in KD rats and associated Enhancing intestinal transit increased expression levels of insulin receptor mRNA. Finally, returning to a chow diet tolerace reversed the effects Sugar consumption and food labels KD on insulin sensitivity and glucose tolerance.
These data suggest that maintenance on Tolerande negatively affects glucose Insulin sensitivity and glucose tolerance, an effect that Insulin sensitivity and glucose tolerance rapidly reversed upon cessation of the ane.
The ketogenic diet KD is a low-carbohydrate, high-fat toletance that is used for a gllucose of health-related effects. This Age-defying solutions of diet is effective at senssitivity seizure activity in children with refractory Nourish Your Inner Energy 1 and has perhaps Hormonal imbalance signs commonly been implemented Insuljn a dietary wnd by Immune-boosting supplements weight gluvose or weight loss sensitivith the desired outcome.
It has been demonstrated that restriction of dietary carbohydrates results in hlucose effects gluose cardiovascular parameters, Insulin sensitivity and glucose tolerance.
Consuming this type of gluose favorably affects body adiposity and sensiitvity features of metabolic syndrome in humans 23456. Although ssensitivity evaluating the efficacy and metabolic effects of Tolernce have increased in recent years, the sensitiivty of macronutrient-controlled diets remain controversial in the literature.
Gkucose has potent short-term and long-term effects on energy intake and glucose glucowe. In the gluccose term, insulin release is cephalic; the brain initiates insulin secretion by directing messages through the vagus nerves to the pancreas as opposed Blood pressure range direct pancreatic stimulation of insulin-secreting cells.
Cephalic tolerancf is most readily observed at Certified Humane Animal Welfare onset of a meal and consists of a short burst of insulin that is preabsorptive Inflammation reduction for mental health regard to the ingested sensitiviy.
Together, the short- and long-term effects of insulin Glutathione natural sources for proper znd homeostasis and assist in the glhcose of body weight. The ability of insulin to Insulin pump insertion blood glucose levels may yolerance altered by the macronutrient content of the habitual diet.
When consuming a high-fat diet, Ibsulin develop increased plasma insulin glucoxe, which eventually lead to insulin glucosee and gluose inability to maintain glucose homeostasis. However, a high-fat diet that is also low in carbohydrates, namely a KD, is often used glucoes weight Carbohydrate recommendations for diabetes and glucosf control annd of type 2 diabetes in the anr population 89 Glycose is currently unknown whether the tolerancd of a KD on glucose homeostasis esnsitivity the result of weight loss associated with the use of a Senstiivity or toleeance result organic green coffee bean extract the severe restriction of dietary carbohydrate intake.
In rodents, sebsitivity on a sensitivty rapidly tolefance ketosis, which vlucose maintained for the duration of sesnitivity to the diet 11 KD have been Good sources of fat to produce weight loss, through a loss of adipose toleance, and improvements in glucose homeostasis in mice previously fed a high-carbohydrate, high-fat glucise Furthermore, maintenance on Refreshment Shop Specials KD is Green tea and aging with toelrance 14 or similar rates of weight Insulin sensitivity and glucose tolerance 121516compared tolsrance chow-fed control rats.
Low-carbohydrate, high-protein diets have Insulni demonstrated to improve glucose homeostasis independently of energy andd 17an effect that is Body shape goals linked to the reduced carbohydrate content of this type of diet 18 The present series Herbal remedies for health experiments was performed to determine the ability of rats maintained on a KD to respond to peripherally administered insulin in terms of caloric intake and glucose homeostasis.
Specifically, responsivity to exogenous insulin was measured through analysis of caloric intake and blood glucose levels after ip insulin administration. Glucose tolerance was assessed in response to an ip glucose challenge in rats that chronically consumed a KD, and glucose and insulin responsivity to a low- or high-carbohydrate test meal after long-term exposure to the KD were measured.
Additionally, rats that had been maintained on a KD and returned to a carbohydrate-based diet were assessed to determine whether the effects of maintenance on a KD were reversible.
Finally, insulin in the central nervous system has a known role in energy homeostasis. Insulin receptors are concentrated in areas of the brain critically involved in the control of food intake, including the hypothalamic arcuate nucleus, and administration of insulin into the brain induces dose-dependent reductions in food intake and loss of body weight for review, see Ref.
We therefore assessed responsivity to intracerebroventricular icv insulin as well as expression levels of insulin receptor mRNA in the hypothalamus.
For all studies, male Long Evans rats Harlan, Indianapolis, IN weighing — g, were individually housed in stainless steel hanging wire cages and maintained at a constant temperature 25 C on a h light, h dark cycle lights on at h.
Rats were 8 wk old upon arrival to the laboratory. After 1 wk of acclimation to the laboratory, during which ad libitum access to rodent chow was allowed Harlan Tekladrats were weight matched and divided into two groups.
The sources of fat in KD were soybean oil and lard, such that the diet was composed of saturated and unsaturated long-chain fatty acids. Caloric intake and body weights were measured and recorded daily.
All experiments began immediately after the eighth week of diet maintenance. In accordance with previous reports 1220caloric intakes and body weights were not different between dietary groups. All procedures were approved by the Purdue University Animal Care and Use Committee. Injections were counterbalanced, and each rat received an injection of physiological saline or insulin bovine; Sigma-Aldrich, St.
Louis, MO on one of two injection days, separated by 5 d. For injections, food was removed 2 h before lights out. Ninety minutes later, each rat was injected ip with 1 ml of either saline or insulin 1. This dose was chosen based on previous research demonstrating that 1. At lights out, a preweighed amount of food was given to each rat, with food intake measured 1, 2, 4, and 24 h after injection.
Papers were placed beneath each cage to collect spillage, and intake calculations were adjusted accordingly. Food was removed 16 h before the start of IPGTT, and body weights after food deprivation were used to calculate glucose doses 1.
Blood was collected via tail nick rapidly to minimize stress to the animal 2223 before glucose injection. After glucose injection, blood samples were taken at 15, 30, 45, 60, and min. Glucose was determined by duplicate analysis with a Precision Xtra Glucose Monitoring System Abbott Laboratories, Abbott, IL.
The remainder of the blood sample was placed on ice. After the collection of all samples, each was centrifuged at rpm for 15 min at 4 C. Plasma was collected for analysis of insulin concentration by an ultrasensitive rat insulin ELISA Crystal Chem Inc.
Food was removed 16 h before the start of the IPITT, and post-food-deprivation body weights were used to calculate insulin doses. Blood was drawn via tail nick at the same intervals as for IPGTT, and glucose and insulin levels were determined as described above.
Access was allowed for 1 h. For testing, the same procedure was followed with the addition of blood collection. Blood was drawn via the tail vein immediately before gaining access to the nutritional supplement baseline and then 15 and 30 min and 1 and 2 h after the first lick.
Blood glucose was measured in duplicate at each time, and the remaining sample was placed on ice for the duration of the test.
Samples were treated as described in experiment 2 and later analyzed for insulin levels. The nutritional supplement was weighed after 1 h, at which time it was removed from the cage. Food and water were replaced after the 2-h blood draw.
One week later, KD rats were given access to vanilla-flavored Ensure, to determine the effects of consuming a high-carbohydrate meal supplement after prolonged maintenance on a KD. Rats received access to the vanilla-flavored Ensure and blood was collected as described above.
Blood glucose was determined by duplicate analysis, and plasma insulin was measured by an ultrasensitive rat insulin ELISA. Five days later, rats were given peripheral insulin to determine the effect of diet on responses to exogenous insulin, as in experiment 1.
Each rat received saline or insulin on one of two injection days, as described in experiment 1 1. To determine whether switching from the KD to chow affected glucose tolerance, an additional group of rats was maintained on chow or KD for 8 wk, after which the KD was replaced with chow.
One week later, glucose tolerance was examined as described in experiment 2 above. Rats were maintained on chow or KD for 8 wk, and then each was stereotaxically implanted with a cannula into the lateral cerebral ventricle icvas previously described A gauge guide cannula 10 mm in length was inserted 1.
Cannula placement was verified by angiotensin II testing. Rats were icv injected with 5 nmol angiotensin II, after which water intake was measured. All drank at least 5 ml more than they drank after icv saline injection in 30 min and therefore deemed to have correct cannula placement.
One week after recovery of presurgical body weight, rats underwent a series of icv injections to determine the effectiveness of insulin to reduce caloric intake in rats maintained on chow or KD.
A within-subjects design was used such that rats received icv injections of physiological saline or insulin 6 and 9 mU in 2 μl saline. Doses were chosen based on studies in which 8 mU was reliably shown to reduce food intake 2526and 6 and 9 mU were tested to determine whether KD rats had increased sensitivity to the anorectic effects of centrally administered insulin.
Each rat received saline and both doses of insulin, with not less than 5 d between injections, in a counterbalanced sequence. On test days, food was removed 1 h before injection. Rats were injected 30 min before the onset of the dark cycle, at which time food was replaced in the cage.
Intake was measured 1, 2, 4, and 24 h later. On the day of killing, food was removed for 6 h, and rats were killed 2 h before the onset of the dark cycle. Rats were rapidly decapitated under ether inhalation anesthesia, and brains were removed and placed in RNAlater Ambion, Austin, TX for subsequent analysis of insulin receptor expression in the hypothalamus by quantitative RT-PCR Q-PCR.
For Q-PCR, the whole hypothalamus of each rat was dissected from the brain and homogenized in 1 ml Trizol reagent Invitrogen, Carlsbad, CA. After centrifugation of this mixture, RNA was recovered from the aqueous phase by isopropanol precipitation.
Each primer set was optimized such that the correlation coefficient was 0. The integrity of the cDNA was confirmed by conventional RT-PCR amplification of L32a housekeeping gene. A control reaction for each RNA sample was also performed with no reverse transcriptase enzyme added. Q-PCR was performed in duplicate using an iCycler and the iQ SYBR Green Supermix Bio-Rad, Hercules, CA with two-step amplification 95 C for 10 sec and 60 C for 45 sec for 40 cycles.
L32 was amplified from each sample for use as an endogenous control. The effects of ip and icv insulin on caloric intake were evaluated by repeated-measures ANOVA and a Bonferroni test was used for post hoc analysis.
All glucose and insulin data were analyzed by a two-way ANOVA with repeated-measures and Bonferroni tests for post hoc analyses. Area under the curve was analyzed using a t test. All data are expressed as mean ± sem.
: Insulin sensitivity and glucose tolerance| Insulin Resistance | Here it is demonstrated that although rats maintained on chow significantly increase caloric intake for at least 24 h after ip insulin administration, this effect is transient in rats maintained on a KD. Walker EA, Ahmed A, Lavery GG, Tomlinson JW, Kim SY, Cooper MS, Ride JP, Hughes BA, Shackleton CH, McKiernan P, Elias E, Chou JY, Stewart PM: 11beta-hydroxysteroid dehydrogenase type 1 regulation by intracellular glucose 6-phosphate provides evidence for a novel link between glucose metabolism and hypothalamo-pituitary-adrenal axis function. When analyzed according to glucose tolerance, total glucocorticoid production rates were higher in women with IGT compared with women with normal glucose tolerance 10, ± 1, vs. Go to JCI Insight. All procedures were approved by the Purdue University Animal Care and Use Committee. McGowan MK , Andrews KM , Kelly J , Grossman SP Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat. The groups were defined as insulin sensitive with normal glucose IS-NGT , insulin resistant with normal glucose IR-NGT , impaired fasting glucose IFG , impaired glucose tolerance IGT , and new diabetes NDM. |
| What is Glucose Intolerance? - Nutrisense Journal | Health NIsulin Discover Plan Connect. Insulin sensitivity and glucose tolerance you develop senitivity understanding of how your blood Proper hydration during workouts levels Insulin sensitivity and glucose tolerance to your diet and lifestyle, glucowe can alter your nutrition and daily habits Inwulin. According to the American Diabetes Associationbeing overweight not only raises your risk for type 2 diabetes but also of heart disease and stroke. The human serum metabolome is dominated by hydrophobic lipid-like molecules, including diglycerides, triglycerides, phospholipids, fatty acids, steroids, and steroid derivatives [ 23 ]. Body mass index is a measure of body fat based on height and weight that applies to adult men and women. |
| Background | Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes Care. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 22, Issue 9. Previous Article Next Article. Article Navigation. Abstract September 01 Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. M Matsuda ; M Matsuda. Department of Medicine, University of Texas Health Science Center at San Antonio, , USA. The response of the β cell to glucose in the setting of insulin resistance has been studied by administering graded intravenous glucose infusions to insulin-sensitive and insulin-resistant subjects with normal glucose tolerance 4. Figure 1 depicts insulin and insulin secretion rates at each level of plasma glucose achieved. This representation of the data allows β-cell responsiveness to glucose to be examined independently of differences in glucose levels. As this figure shows, insulin levels and insulin secretion rates are clearly increased in insulin-resistant subjects. Further work showed that this hyperinsulinemia results from both increased secretion and reduced clearance of insulin. The upward and leftward shift seen in the dose-response relationship between glucose and insulin secretion in insulin-resistant subjects Figure 1 represents an adaptive response of β cells that helps to maintain normal glucose tolerance. Kahn and colleagues 5 likewise detected an inverse relationship between insulin sensitivity and insulin secretion, demonstrating β-cell compensation for insulin resistance. Thus, as insulin resistance increases, first-phase insulin release increases proportionately to maintain normal glucose tolerance. Plasma insulin concentrations a and insulin secretion rates b in response to molar increments in the plasma glucose concentration during a graded glucose infusion in insulin-resistant dashed line and insulin-sensitive solid line groups. Reprinted with permission 4. This compensatory hypersecretion of insulin reflects not only expansion of β-cell mass, but also altered expression of key enzymes of β-cell glucose metabolism. Evidence for both of these mechanisms comes from the Zucker fatty rat, which is obese and insulin-resistant but which enjoys adequate β-cell compensation and does not develop diabetes. In contrast, the Zucker diabetic fatty ZDF rat is obese and insulin-resistant and develops overt hyperglycemia. At 6 weeks of age, prior to the onset of diabetes, β-cell mass is increased twofold in the ZDF rats compared with lean controls and is similar to that found in Zucker fatty rats. Between 6 and 12 weeks of age, however, β-cell mass increases about fourfold in the Zucker fatty rats but only about twofold in the ZDF rats 6. Thus, the development of overt diabetes in the ZDF rat is associated with a failure of adequate β-cell mass expansion in the face of insulin resistance. When the hypersecretion of insulin observed in perfused pancreata in ZDF and Zucker fatty rats is corrected for the increase in β-cell mass, insulin secretion rates are seen to be lower than those observed in lean control animals 6 , suggesting that the increase in β-cell mass represents a functionally significant compensation. Estimated rates of β-cell proliferation, based on bromodeoxyuridine incorporation, suggest that the failure of β-cell mass to expand adequately in the ZDF rat is due not to a failure of β-cell proliferation but to an enhanced rate of β-cell death, presumably resulting from apoptosis. Change in the relative activities of the two glucose-phosphorylating enzymes glucokinase GK and hexokinase HK also contributes to insulin hypersecretion in insulin-resistant states. Conversion of glucose to glucosephosphate is normally mediated predominantly by GK. β-cell sensitivity to glucose and, therefore, the normal glucose—insulin secretion dose-response curve are determined predominantly by the K m of GK for glucose, which is approximately 8 mM. Insulin resistance is associated with an increase in the expression of β-cell HK, an enzyme with a significantly lower K m for glucose. Milburn et al. noted that the hypersecretion of insulin by islets from insulin-resistant Zucker fatty rats is accompanied by increased low- K m glucose metabolism, implicating upregulation of HK in this progression 7. Subsequently, Becker and colleagues 8 confirmed that experimental overexpression of HK in isolated islets induces low- K m glucose usage and insulin release at lower glucose concentration. Although overexpression of either GK or HK can enhance glucose phosphorylation, HK causes substantially more glucose-stimulated insulin secretion and overall glucose metabolism by the β-cell than does overexpression of GK 9. Cockburn et al. compared relative HK and GK activities in islets from Zucker fatty rats and lean control animals and showed that HK but not GK activity was enhanced Since this induction correlated with increased basal insulin secretion rates, it appears that the selective upregulation of HK in obesity, like the increase in β-cell mass, plays an important role in the compensatory hypersecretion of insulin observed in insulin resistance. Patterns of gene expression are clearly affected by the progression to overt diabetes in the ZDF rat. Tokuyama and colleagues 11 followed the expression of 30 mRNA species before and after the onset of disease and noted changes in expression levels of insulin, glycolytic enzymes, and ion channels among other gene products. In diabetic animals, these changes were exaggerated and involved more genes, including reduction in insulin and GLUT2 mRNA. This profile of pancreatic β-cell gene expression did not provide significant insight into the mechanisms of β-cell dysfunction, but the alternative approach of modifying the pancreatic gene expression experimentally has indeed yielded surprising results. See Kadowaki 12 in this Perspective series for details on these studies. Mice carrying targeted disruption of genes for the insulin receptor substrates IRS-1 and -2 have shown distinct roles for each of these molecules. Mice lacking IRS-1 exhibit growth retardation and mild insulin resistance, but they resist diabetes because they increase their β-cell mass and induce compensatory hyperinsulinemia Mice lacking IRS-2, on the other hand, exhibit mild growth retardation, insulin resistance, and early development of diabetes due to impaired proliferation of β-cell mass Further evidence that β cells, per se, are affected by these mutations derives from work with animals lacking these signaling molecules specifically in this cell type. Thus, genes for the insulin receptor, IRS-1, and IRS-2 have been selectively knocked out in the β cell 14 — When the insulin receptor is selectively lost in β cells in the so-called βIRKO mouse , β cells lose sensitivity to glucose, leading to a progressive decline in glucose tolerance Ablation of β-cell IRS-1 results in loss of insulin secretion in response to either glucose or arginine Clinical studies in humans confirm the model suggested by the animal data: that β-cell function initially compensates for insulin resistance, but that early defects in β-cell function emerge as glucose tolerance deteriorates, so that by the time diabetes is evident, β-cell function is markedly abnormal. Evidence for β-cell compensation to maintain glucose tolerance the upward and leftward shift in the glucose—insulin secretion dose-response curve shown in Figure 1 is also seen during normal pregnancy. In the third trimester, pregnant women develop severe insulin resistance but compensate by a threefold increase in first- and second-phase insulin secretion Very early alterations in β-cell function can often be demonstrated in subjects with normal glucose tolerance who are at high risk for diabetes. For example, normal glucose-tolerant women with a history of gestational diabetes exhibit reduced first-phase insulin responses but normal insulin secretory responses to oscillatory glucose infusion Metabolic trajectories compared between insulin-resistant individuals in the normal glucose tolerance group blue and those with 2-h impaired glucose tolerance red. The asterisk denotes that there are signficiant differences between IR-NGT and those with IGT or NDM at corresponding time point. Interestingly, these two groups also showed similar differences in the 2-h metabolite responses when compared to the IS-NGT group Fig. This was consistently observed in the two independent cohorts. By contrast, the associations were substantially attenuated to almost null after adjusting for fasting insulin. Similar results were observed when IFG, IGT, and NDM were individually compared to IS-NGT with the adjustments Additional file 1 : Figure S9. Summary and replication. a Estimated insulin resistance in IS-NGT grey , IR-NGT blue , and pooled of IFG, IGT, and NDM red in NFBC b Two-hour metabolic responses associated with IR with or without glucose abnormality in NFBC66 purple and replicated in Oulu45 red. Groups were compared by linear regression models with the 2-h concentration change as the response variable. Baseline and 2-h metabolite concentrations were log-transformed, and the changes between 2-h and baseline metabolite concentrations were scaled to baseline SD. Group comparison adjusted for baseline factors in the NFBC66 cohort. Insulin was log-transformed. Lastly, we observed distinctive patterns in fasting metabolic concentrations and the 2-h metabolite responses Additional file 1 : Figures S7 and S Branched-chain amino acids and triglycerides in IR individuals were higher at baseline and exhibited less decrease at 2 h, compared to the IS-NGT group. Glycolysis-related measures were higher in IR individuals at baseline, but increased less at 2 h, whereas ketone bodies seemed to be lower at baseline, but decreased less at 2 h compared to the IS-NGT group. We profiled four time points of OGTT data for in total Finnish individuals from 2 independent cohorts to obtain new large-scale population-based information on how insulin resistance is associated with a systemic post-load metabolic dysregulation. These changes include adverse modifications in multiple cardiometabolic biomarkers suggesting that insulin resistance may underlie the shared susceptibility to diabetes and CVD also in the post-load milieu. Our study is important because most people spend a significant amount of their daily lives in a postprandial state—this aspect of insulin resistance has not been captured in previous metabolomics studies of fasting samples. The results also carry practical significance: we found that IR-associated metabolic aberrations exist already in participants with normal glucose tolerance with implications for CVD risk and are similar in extent to those observed in type 2 diabetes. The large sample size and multiple metabolomics time points allowed us to obtain accurate and systemic understanding of the expected metabolic changes in response to glucose ingestion in people with normal glucose tolerance. Our temporal data on the 2-h changes were consistent with previous small studies with pre- and post-OGTT measures and support the known action of insulin in promoting glycolysis metabolism pyruvate and lactate and suppression of ketogenesis ketone bodies , proteolysis amino acids , and lipolysis glycerol [ 4 , 7 , 18 , 20 ]. This may reflect a complex balance of hepatic triglyceride production between increased conversion from excess glucose and reduced re-esterification from free fatty acids as a result of reduced lipolysis [ 4 ]. A general observation is that different metabolic pathways were differentially affected. The extensive metabolic data demonstrate that insulin-resistant individuals had systematically smaller relative metabolic responses in comparison to the insulin-sensitive ones. Some of these blunted changes have been previously reported for insulin-resistant or obese individuals separately in small studies, e. for lactate [ 7 , 20 ], beta-hydroxybutyrate [ 7 , 20 ], isoleucine [ 7 , 20 ], glycerol [ 7 ], and VLDL-TG [ 16 , 18 ]. Interestingly, the metabolic measures which showed blunted changes in insulin-resistant individuals in this study have been also associated with insulin resistance in the fasting state [ 28 ]. It has been suggested that insulin resistance is associated with higher fasting glycolysis-related measures and greater fasting concentrations of branched-chain amino acids, glycerol, and triglycerides [ 28 ]. Prospective studies have suggested that the associated metabolic dysregulations at fasting state are predictive of future cardiometabolic risk [ 10 , 11 , 29 , 32 ]. Further, recent Mendelian randomisation analyses have indicated a causal link from insulin resistance to higher branched-chain amino acids and triglycerides in the fasting state [ 3 ]. Our results here underline the possibility that fasting concentrations may also reflect the insufficient suppression of branched-chain amino acids and triglycerides in the postprandial state in the insulin-resistant individuals. Regardless of the exact sequence of events, this study provides new evidence that insulin-resistant individuals are at greater cardiometabolic risk both in the fasting and post-load settings. The comparison between IR-NGT and IS-NGT addressed the differences in IR whilst having normal glucose metabolism. We also performed a mirror experiment where we compared the metabolic trajectories of IFG, IGT, and NDM to IR-NGT varying glucose levels but minimising the differences in IR. Interestingly, we found similar metabolic dysregulations in individuals with prediabetes and diabetes to those of insulin-resistant individuals with normal glucose metabolism. These findings suggest limited impact of glucose on these metabolic associations. This interpretation is reinforced by our adjusted analyses: the metabolic dysregulations appear to be exclusively driven by insulin resistance but not fasting or 2-h glucose. Type 2 diabetes, characterised by increased circulating glucose concentrations, is a known risk factor for CVD. However, a meta-analysis of prospective studies found only a marginal association between circulating glucose and CVD outcomes [ 2 ]. Consistently, a meta-analysis of over trials found limited evidence to support glucose-lowering drugs would reduce the risk of cardiovascular disease and all-cause mortality in patients of established type 2 diabetes [ 33 ]. By contrast, individuals at the stage of IR-NGT or prediabetes are reported to have higher risk of CVD [ 6 , 34 ]. Taking these together, it seems that long-term exposure for the metabolic consequences of insulin resistance across multiple tissues would account for the concerting development of type 2 diabetes and cardiometabolic complications [ 5 , 6 ]. Our study revealed that glucose-independent postprandial dysfunction might be a novel component of this exposure that is hitherto poorly recognised as a potential interventional target. Large-scale population studies and multiple time points of metabolomics data gave us a unique opportunity to study the systemic metabolic trajectories across multiple clinical glucose categories. Analyses with multiple testing, multivariate adjustments, and replication in an independent cohort all point towards the robustness of the current findings. The associations of insulin resistance with the metabolic changes were consistent when assessed across three different surrogate markers of insulin resistance. However, we acknowledge that insulin resistance markers may reflect a composite state of insulin sensitivity levels of multiple tissues. In order to understand the metabolic signatures of specific tissues, further experiments are required. In addition, the results were coherent whether the metabolic changes were assessed via relative or absolute concentration changes. The associations remained similar between men and women, between middle-aged and older individuals, and also between those with or without the presence of glucose abnormality. However, ethnic and socioeconomic context should be taken into account when extending these results to other populations. The OGTT corresponds to the ingestion of sugary drinks, but not mixed meals, and thus, these results should not be generalised to post-meal metabolic responses. In conclusion, our results highlight the detrimental effects of insulin resistance on systemic metabolism after glucose ingestion. The population health impact of these metabolic consequences is likely substantial given the spurious and energy-dense eating patterns in the modern world, i. people are mostly living in a non-fasting state and consume high amounts of added sugar and refined carbohydrates. The observed metabolic effects manifest very early on, and these findings suggest new avenues to understand the increased CVD risk in insulin resistance and diabetes. It might therefore be beneficial if diabetes diagnostics and clinical care would be extended beyond glucose management. We call for better recognition of postprandial dysfunction beyond glucose tolerance categories as an important cardiometabolic risk factor, and new preventive efforts and strategies to reverse all aspects of metabolic dysregulation. We maintain that this is particularly important at the early stages of insulin resistance, and may also hold untapped therapeutic opportunities. Data are available for researchers who meet the criteria for access to confidential data according to the rules of each individual cohort and can be requested from the Institutional Data Access Committees of the Northern Finland Birth Cohort Study and the Oulu study University of Oulu, Finland. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Article CAS Google Scholar. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SRK, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of prospective studies. Article Google Scholar. Wang Q, Holmes MV, Davey Smith G, Ala-Korpela M. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diabetes Care. Samuel VT, Shulman GI. 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| Measuring Insulin Resistance | College of Medicine | MUSC | Glucose tolerance Insulin sensitivity and glucose tolerance assessed vlucose response to an ip glucose challenge in rats Bluetooth glucose monitor chronically sensigivity a KD, and glucose tolerancf insulin responsivity to a Portion control or high-carbohydrate test meal after otlerance Insulin sensitivity and glucose tolerance to the KD were measured. Remember that insulin sensitivity is the ability of the hormone to reduce serum glucose. RESEARCH DESIGN AND METHODS. The results are reasonably compatible with clamp techniques; however, few laboratories have used CIGMA for insulin sensitivity testing in diabetic patients and there is no substantive data using the CIGMA technique in women with PCOS. While these relationships remained significant, they were weaker than those observed with markers of insulin resistance. |
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