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Insulin resistance (IR), a metabolic risk factor, is linked to the pathogenetic mechanism of primary hypertension. Detecting IR in the patients with hypertension will help to predict and stratify the added cardiovascular risk, institute appropriate IR management, and manage hypertension optimally. There are many methods for assessing IR, each with distinct advantages and disadvantages. The euglycemic insulin clamp and intravenous glucose tolerance test, gold standards for measuring IR, are used in research but not in clinical practice. Homeostatic model assessment (HOMA‐IR), a method for assessing β‐cell function and IR, is frequently applied presently, particularly in Asia. Besides, the triglyceride–glucose index (TyG) first published by South American authors showed a good correlation with the insulin clamp technique and HOMA‐IR index. This simple, convenient, and low‐cost TyG index is of research interest in many countries in Asia and can be used to screen for IR in the Asian hypertensive community.

The effects of exogenous insulin, with euglycemia, on the concentration differences, extraction ratio and uptake of 3- hydroxybutyrate and plasma free fatty acids by the lactating sheep hind limb were studied. Generally, the results showed that with increasing plasma insulin levels, while maintaining euglycemia, the concentrations, arterio-venous concentration differences, extraction ratio and uptake of 3-hydrubutyrate and free fatty acids Were significantly (P

Purpose Skeletal muscle is the primary site for insulin-stimulated glucose disposal, and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin-resistant obese humans is controversial. Methods We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 nonobese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 nonobese and 25 obese male and female volunteers matched for fitness using a 1-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2). Results Insulin-stimulated glucose disposal (Si) was reduced by > 60% (P < 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between nonobese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the nonobese (r = 0.53, P = 0.03) and the obese (r = 0.55, P = 0.01) groups. Total muscle GLUT4 protein was 17% less (P < 0.05) in obese subjects. Conclusions We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significant gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity do not replicate the pathophysiology of obesity.

Objective Increased deposition of the extracellular matrix (ECM) in adipose tissue (AT) during obesity contributes to insulin resistance. The integrin receptors transmit changes in the extracellular environment causing corresponding intracellular adaptations. Integrin-linked kinase (ILK), an adaptor protein, is a central hub for intracellular signaling of integrins. This study determined the role of ILK in adipose function and insulin resistance. Methods The pathogenic role of ILK in obesity and insulin resistance was studied in human adipose tissue and adipocyte-specific ILK-deficient mice (ILKlox/loxAdCre). ILKlox/loxAdCre mice together with wild-type littermates (ILKlox/lox) were fed a chow diet or 60% high-fat (HF) diet for 16 weeks. In vivo insulin sensitivity was determined by hyperinsulinemic-euglycemic clamps. Results AT ILK expression was increased by HF diet feeding in mice and increased in visceral fat of morbidly obese humans. The HF-fed ILKlox/loxAdCre mice displayed reduced fat mass and improved glucose tolerance relative to the HF-fed ILKlox/lox mice. During a hyperinsulinemic-euglycemic clamp, the HF-fed ILKlox/loxAdCre mice exhibited partially improved insulin resistance in AT. Lipolysis was suppressed to a greater extent by insulin and glucose uptake in brown AT (BAT) increased. Increased inhibition of lipolysis may have been attributed to increased vascularization in white AT, while increased glucose uptake in BAT was associated with increased Akt phosphorylation and P38/JNK dephosphorylation. Notably, AT insulin sensitivity in lean mice was not affected by ILK deletion. Moreover, reduced fat mass in the HF-fed ILKlox/loxAdCre mice may have been attributed to decreased free fatty acid uptake into adipocytes via the downregulation of CD36 gene expression. Consistent with the results in the mice, knockdown and knockout of ILK in 3T3-L1 cells decreased lipid accumulation and CD36 gene expression during adipogenesis. Conclusions These data show that adipocyte ILK is important for regulating HF diet-mediated insulin resistance in AT in a manner consistent with AT function., Highlights • ILK protein increased in visceral adipose tissue of obese humans and mice. • Mice lacking adipocyte ILK had less fat and improved glucose tolerance in obesity. • Adipocyte ILK deletion improved anti-lipolytic action of insulin in obese mice. • Adipocyte ILK deletion stimulated brown adipose tissue glucose uptake in obese mice.

Background: Applying the hyperinsulinemic-euglycemic clamp to estimate insulin resistance (IR) is accurate but time-consuming, so identifying a simple and effective index for IR is vitally...

Operatively induced inflammation has been the focus of many studies to evaluate the most efficient responses and protocols to be used for its control. Insulin has been characterized with nonmetabolic properties and is used as a preoperative anti-inflammatory agent. We reviewed the published evidence in the past 10 years reporting on the use of glucose–insulin-normoglycemia therapy as a potential anti-inflammatory therapy to improve surgical outcomes about tissue trauma, with the challenges and progress attenuated so far. We also portray our experience in the use of insulin therapy on our liver resection patients as well as the significant knowledge gaps that still exist and the need for a multidisciplinary approach to bridge them.

Background: Fasting insulin resistance indexes are used extensively nowadays. We intended to analyze a new recently presented fasting index, SPISE (sensitivity formula: 600 x HDL-cholesterol(0.185)/triglycerides(0.2)/BMI1.338), in comparison with three previously known fasting indexes, regarding correlation with the insulin clamp index, and for the predictive effects of future long-term risks of coronary heart disease (CHD) or manifest type 2 diabetes. Methods: A total of 1049 71-year-old male subjects from the Swedish ULSAM study, median follow-up 8 years, were included. All subjects performed the euglycemic insulin clamp, and analyses of four fasting insulin resistance indexes: SPISE-IR (= 10/SPISE), QUICKI-IR, Log HOMA-IR, and Revised QUICKI-IR. Results: Spearman correlation coefficients with the insulin clamp were 0.60-0.62 for all indexes. Area under curve at ROC analysis was 0.80 for SPISE-IR, and 0.84 for QUICKI-IR, Log HOMA-IR, and Rev QUICKI-IR. Adjusted hazard ratios per 1 SD index increase for long-term risk CHD were similar in all patients: 1.20-1.24 (p = 0.02-0.03). However, comparing the highest quartile (recommended to define insulin resistance) with the lower quartiles, SPISE-IR was the strongest and the only statistically significant insulin resistance index: HR 1.53 (p = 0.02). Adjusted odds ratios per 1 SD index increase for long-term risk of type 2 diabetes were fairly similar (p < 0.001) in all patients: 1.62 for SPISE-IR, 1.97 for QUICKI-IR and Log HOMA-IR, and 2.04 for Rev QUICKI-IR, and also when comparing the highest versus the lower quartiles: 2.8-3.1 (p < 0.001). Conclusion: SPISE, easily applicable, performed equally well as other fasting insulin indexes previously recommended for clinical use, regarding correlation with the insulin clamp, and as predictor for future long-term risks of CHD or type 2 diabetes.

IntroductionHepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes. HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. However, hyperglycemia was suggested to enhance HIC, and it is not known whether poorly controlled diabetes increases HIC in patients with type 2 diabetes. We investigated whether HIC was increased in patients with poorly controlled diabetes, and whether HIC was associated with insulin resistance and incretins.Research design and methodsWe performed a meal tolerance test and the hyperinsulinemic–euglycemic clamp in 21 patients with type 2 diabetes. We calculated the postprandial C-peptide area under the curve (AUC)-to-insulin AUC ratio as the HIC; measured fasting and postprandial glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon levels and analyzed serum adiponectin and zinc transporter-8 (ZnT8) gene polymorphism.ResultsThe HIC significantly correlated with glycated hemoglobin (HbA1c) (r_S=0.58, pr_S=−0.77, pr_S=−0.66, pConclusionsThese results suggest that HIC was increased in patients with high HbA1c type 2 diabetes, low insulin secretion, low insulin resistance and high adiponectin conditions.

In 2007, a novel estimate of skeletal muscle insulin sensitivity was derived from the oral glucose tolerance test (OGTT). The aim of this investigation is to assess whether and to what extent the proposed index of skeletal muscle insulin sensitivity derived from the OGTT was associated with muscle insulin sensitivity measured using the hyperinsulinemic-euglycaemic clamp technique.Forty-six middle-aged, abdominally obese men (age 44 ± 8 years, waist circumference 107.4 ± 6.2) were studied. Each participant participated in a 2-hour, 75-g OGTT and a 3-hour hyperinsulinemic-euglycaemic clamp protocol.The OGTT-derived index of muscle insulin sensitivity correlated with muscle insulin sensitivity measured with the insulin clamp (r=0.55, P0.01), however, the standard error of estimate (SEE) when predicting muscle insulin sensitivity by the OGTT-derived index was 5.3 (50%).Our findings suggest that despite a statistically significant association between the two methods, the OGTT approach lacks precision and is not a useful method for estimating skeletal muscle insulin sensitivity in abdominally obese men.

Hypoglycemia and/or fear of hypoglycemia are major challenges for many with type 1 diabetes (T1D), limiting ability to lower glycemia. Given anecdotal reports of domestic pets alerting owners to blood glucose changes, especially hypoglycemia (1), we hypothesized that volatile organic compounds (VOCs) in exhaled breath might change at low glucose. We studied eight female nonsmoking participants with T1D (aged 46 ± 5 years, diabetes duration 23 ± 7 years, none treated with statins) twice using a single-blinded, computer code–randomized crossover design. An independent research ethics committee approved studies in advance, and subjects provided written consent. Using a stepped insulin clamp (Actrapid; Novo Nordisk, Crawley, U.K.; 0.3 mU/kg/min increasing to 1.5 mU/kg/min), on one occasion (STEP), arterialized plasma glucose (Yellow Springs Instrument 2300 STAT Plus Analyzer) was raised sequentially (7.1 ± 0.8, 8.7 ± 0.4, and 10.7 ± 0.1 mmol/L) then lowered with higher insulin infusion to 4.3 ± 0.3 and 2.8 ± …

Aims: To clarify the relationship between depression and glucose metabolism using sensitive measures of insulin resistance, and to assess if remission of depression results in enhanced insulin sensitivity. Methods: An intervention study to quantify changes in insulin sensitivity before and after treatment of depression was carried out. Twenty six Pakistani women with newly diagnosed depression underwent euglycemic insulin clamp to measure insulin sensitivity at inclusion and again after treatment of depression 6 - 8 weeks later. Twenty-three individuals completed both tests. Results: Significant improvement of insulin sensitivity was observed following the treatment of depression. The improved insulin sensitivity remained statistically significant after controlling for confounding factors. Conclusions: This study establishes a relationship between depression and insulin resistance. It demonstrated that insulin sensitivity can be improved by treating depression.

ApoE is a polymorphic protein involved in the metabolism of plasma lipoproteins; the e4 allele was shown to be associated with coronary and aortic atherosclerosis in age-dependent fashion mediated by unknown mechanisms. This study was undertaken to assess whether the apoE isoforms in humans were associated with normal glucose tolerance and with metabolic and inflammatory risk factors of CVD. ApoE genotype was assessed in 365 individuals. Of those, 309 were studied in the postabsorptive conditions and 142 of them also underwent a 3h-OGTT; 56 additional subjects were studied by means of the insulin clamp in combination with [6,6-2H2] glucose infusion. ApoE genotype frequencies were similar to those previously reported and were not influenced by age and BMI. Fasting plasma glucose, insulin, FFA, the lipid profile, surrogate markers (HOMA-IR, OGTT-derived index) as well as the clamp-derived parameters or insulin sensitivity and insulin secretion were not different by apoE genotypes. Serum adipokines concentrations (leptin, adiponectin, resistin) and markers of inflammation (serum fasting hsCRP and MCP1/CCL2) were also not different by apoE genotypes. In the subgroup of young e4 carriers which underwent the clamp procedure, a higher fasting endogenous glucose production was detected. ApoE genotype was not associated with insulin resistance or altered insulin secretion, and no abnormalities in the typical circulating endocrine, metabolic, and inflammatory features of the insulin resistance syndrome were detected. © Springer-Verlag 2011

This article addresses two topics. We provide an overview of the National Institutes of Health Mouse Metabolic Phenotyping Center (MMPC) Program. We then discuss some observations we have made during the first eight years of the Vanderbilt MMPC regarding common phenotyping practices. We include specific recommendations to improve phenotyping practices for tests of glucose tolerance and insulin action. We recommend that methods for experiments in vivo be described in manuscripts. We make specific recommendations for data presentation, interpretation, and experimental design for each test. To facilitate and maximize the exchange of scientific information, we suggest that guidelines be developed for methods used to assess glucose tolerance and insulin action in vivo.

To understand the underlying pathology of metabolic diseases, such as diabetes, an accurate determination of whole body glucose flux needs to be made by a method that maintains key physiological features. One such feature is a positive differential in insulin concentration between the portal venous and systemic arterial circulation (P/S-IG). P/S-IG during the determination of the relative contribution of liver and extra-liver tissues/organs to whole body glucose flux during an insulin clamp with either systemic (SID) or portal (PID) insulin delivery was examined with insulin infusion rates of 1, 2, and 5 mU·kg−1·min−1 under either euglycemic or hyperglycemic conditions in 6-h-fasted conscious normal rats. A P/S-IG was initially determined with endogenous insulin secretion to exist with a value of 2.07. During an insulin clamp, while inhibiting endogenous insulin secretion by somatostatin, P/S-IG remained at 2.2 with PID, whereas, P/S-IG disappeared completely with SID, which exhibited higher arterial and lower portal insulin levels compared with PID. Consequently, glucose disappearance rates and muscle glycogen synthetic rates were higher, but suppression of endogenous glucose production and liver glycogen synthetic rates were lower with SID compared with PID. When the insulin clamp was performed with SID at 2 and 5 mU·kg−1·min−1 without managing endogenous insulin secretion under euglycemic but not hyperglycemic conditions, endogenous insulin secretion was completely suppressed with SID, and the P/S-IG disappeared. Thus, compared with PID, an insulin clamp with SID underestimates the contribution of liver in response to insulin to whole body glucose flux.

Objective To determine the relation between blood pressure and insulin resistance in children and the differences between fasting insulin and the insulin clamp in that relation. Methods Children were randomly selected after blood pressure screening of 12 043 fifth–eigth grade Minneapolis, Minnesota, students, with stratification by systolic blood pressure (SBP) percentile [half from the upper 25th percentile (high blood pressure) and half from the lower 75th percentile (low blood pressure)]. Euglycemic insulin clamps were performed with an insulin infusion rate of 1 mU/kg per min and a variable infusion of 20% glucose to maintain plasma glucose at 5.6 mmol/l (100 mg/dl). Insulin sensitivity (Mlbm) is defined as the amount of glucose required to maintain euglycemia (mg glucose infused/kg lean body mass (LBM)/min. Results Diastolic blood pressure was not significantly correlated with any of the body measurements or laboratory data. SBP was significantly correlated with virtually all measures of body size in males and females. SBP and Mlbm were not significantly correlated in either sex. The correlation between SBP and fasting insulin was significant for boys and girls, but became non-significant after adjustment for BMI. All measures of body fatness were significantly greater in the high blood pressure group, and a significant clustering effect for fasting insulin, BMI, triglycerides, and HDL-C was related to blood pressure. The clustering effect was similar when Mlbm was substituted for fasting insulin and was similar for boys, girls, blacks and whites. Conclusions These results suggest that level of blood pressure in children is mediated through body fat and that insulin resistance, as determined by the insulin clamp, does not play a primary role at this age of development. Nevertheless, the clustering effect of the risk factors according to SBP grouping is consistent with an early relation of blood pressure to the insulin resistance syndrome.

International audience; Epidemiological and experimental evidence suggests that a suboptimal environment during perinatal life programs offspring susceptibility to the development of metabolic syndrome and Type 2 diabetes. We hypothesized that the lasting impact of perinatal protein deprivation on mitochondrial fuel oxidation and insulin sensitivity would depend on the time window of exposure. To improve our understanding of underlying mechanisms, an integrative approach was used, combining the assessment of insulin sensitivity and untargeted mass spectrometry-based metabolomics in the offspring. A hyperinsulinemic-euglycemic clamp was performed in adult male rats born from dams fed a low-protein diet during gestation and/or lactation, and subsequently exposed to a Western diet (WD) for 10 wk. Metabolomics was combined with targeted acylcarnitine profiling and analysis of liver gene expression to identify markers of adaptation to WD that influence the phenotype outcome evaluated by body composition analysis. At adulthood, offspring of protein-restricted dams had impaired insulin secretion when fed a standard diet. Moreover, rats who demonstrated catch-up growth at weaning displayed higher gluconeogenesis and branched-chain amino acid catabolism, and lower fatty acid β-oxidation compared with control rats. Postweaning exposure of intrauterine growth restriction-born rats to a WD exacerbated incomplete fatty acid β-oxidation and excess fat deposition. Control offspring nursed by protein-restricted mothers showed peculiar low-fat accretion through adulthood and preserved insulin sensitivity even after WD-exposure. Altogether, our findings suggest a testable hypothesis about how maternal diet might influence metabolic outcomes (insulin sensitivity) in the next generation such as mitochondrial overload and/or substrate oxidation inflexibility dependent on the time window of perinatal dietary manipulation.

Familial combined hyperlipidemia (FCH) is a heterogeneous lipid disorder, caused by overproduction of VLDL and characterized by the occurrence of small, dense LDL particles, all features that are also associated with insulin resistance. Therefore, insulin sensitivity was examined directly by means of the euglycemic hyperinsulinemic clamp technique in male nonobese, normotensive FCH patients and compared with that of their nonaffected relatives, matched for age and body mass index (BMI). In addition, an oral 75-g glucose tolerance test (OGTT) was performed and lipid values, including the LDL subfraction profile, were determined. During the clamp, forearm blood flow (FBF) was measured by venous occlusion plethysmography. All participants had a normal glucose response after the glucose load, whereas FCH patients showed hyperinsulinemia after OGTT and higher fasting C-peptide levels. During the clamp, insulin concentrations increased equally in both groups. Mean whole-body glucose uptake (M) (120 to 180 minutes) was lower in FCH patients than in nonaffected relatives (6.89±0.31 versus 8.94±0.76 mg • kg -1 • min -1 ; P =.01). In addition, the glucose uptake per unit insulin (I) was lower in FCH patients (insulin sensitivity index [M/I], 7.46±0.50 versus 9.51±0.53; P =.009). M significantly correlated with BMI, plasma cholesterol and triglyceride concentrations, and the individual LDL density. The FBF correlated with insulin sensitivity and increased significantly in nonaffected relatives (1.9±0.12 to 2.5±0.4 mL • min -1 • dL -1 ; P =.025) but not in patients. Thus, FCH patients characterized by a predominance of small, dense LDL are insulin resistant compared with their nonaffected relatives. This insulin resistance may partly be explained by a decreased insulin-induced vasodilation in skeletal muscle. ( Arterioscler Thromb Vase Biol. 1997;17:1465-1471.)

A modified method for performance of insulin-glucose clamp studies in rats was developed via catheterization of the tail vessels, after preconditioning of animals to limited restraint. The procedure is performed in conscious animals under local anesthesia and employs a specially designed foam rubber jacket which allows the animal mobility of the limbs and forward vision. In addition, a table utilizing a belt system allows easy positioning of the animal in the left and right lateral and supine positions during surgery. After initial development of the procedure, its use in 123 animals is reported. Line placement was successfully achieved in all cases with insignificant blood loss or morbidity and zero mortality. We note that 11% of animals did not complete the subsequent insulin-glucose clamp study due to either one of the vascular cannulae leaving the vessel (one animal), venous rupture (12 animals), or cannula blockage unrelated to surgical technique (one animal). Studies on Wistar Kyoto, Spontaneously Hypertensive, and Sprague-Dawley rats showed a fall in catecholamines after animals were replaced in cages, with stabilization within 30 min. In comparison to traditional techniques, this method is, therefore, proposed as a less traumatic and rapid way of performing infusion studies in conscious rats with a high success rate and minimization of loss of animal life due to procedural problems.

Introduction. Seasonal variations in hemoglobin-A1c have been reported in diabetic patients, but the underlying mechanisms have not been elucidated. Aims. To study if insulin sensitivity, insulin secretion, and fasting plasma glucose showed seasonal variations in a Swedish population-based cohort of elderly men. Methods. Altogether 1117 men were investigated with a euglycemic insulin clamp and measurements of fasting plasma glucose and insulin secretion after an oral glucose tolerance test. Values were analyzed in linear regression models with an indicator variable for winter/summer season and outdoor temperature as predictors. Results. During winter, insulin sensitivity (M/I, unit = 100 × mg × min-1 × kg-1/(mU × L-1)) was 11.0% lower (4.84 versus 5.44, P = 0.0003), incremental area under the insulin curve was 16.4% higher (1167 versus 1003 mU/L, P = 0.007). Fasting plasma glucose was, however, not statistically significantly different (5.80 versus 5.71 mmol/L, P = 0.28) compared to the summer season. There was an association between outdoor temperature and M/I (0.57 units increase (95% CI 0.29–0.82, P < 0.0001) per 10°C increase of outdoor temperature) independent of winter/summer season. Adjustment for life-style factors, type 2 diabetes, and medication did not alter these results. Conclusions. Insulin sensitivity showed seasonal variations with lower values during the winter and higher during the summer season. Inverse compensatory variations of insulin secretion resulted in only minor variations of fasting plasma glucose. Insulin sensitivity was associated with outdoor temperature. These phenomena should be further investigated in diabetic patients.

The effects of daily physical activity on peripheral insulin action were investigated in aged individuals. Glucose infusion rates (GIR) during the euglycemic insulin clamp procedure in aged bedridden, aged controls, and aged athletes were compared with those in young controls and young athletes at insulin infusion rates of 40 and 400 mU.m-2.min-1 to estimate insulin action at physiological and maximal insulin concentrations, respectively. At both insulin infusion rates, GIR was significantly higher in aged athletes and significantly lower in aged bedridden subjects than in aged controls. Although there was no statistical difference in GIR at 400 mU.m-2 x min-1 between young athletes and young controls, GIR at 40 mU.m-2 x min-1 was higher in young athletes than in young controls. Comparison of the aged and young groups showed that although GIR at 400 mU.m-2 x min-1 was significantly lower in aged controls than in young controls, there was no significant difference between the aged athletes and the young athletes. We conclude that insulin responsiveness (insulin action at the postreceptor binding site) may decrease with the aging process and may be further affected by physical inactivity. Although physical training may improve insulin responsiveness in aged individuals up to levels similar to those in young athletes, physical training in young individuals may improve only insulin sensitivity.

Conventional wisdom is that breath acetone may be markedly elevated in type 1 diabetes, but that this only occurs during poor blood glucose control and/or intercurrent illness. In contrast, little is known about breath acetone at more representative everyday blood glucose levels in diabetes. We used selected ion flow tube mass spectrometry (SIFT-MS) to monitor the breath of 8 patients with type 1 diabetes mellitus during “insulin clamp” studies in which insulin and glucose were infused into patients to lower blood glucose levels in steps from normal values into the low glucose (hypoglycaemic) range. The concentration of acetone in breath and the blood sugar concentration of the patients were monitored at each blood glucose concentration. The blood glucose level at the start of the study was typically about 6mM/L, whereas the breath acetone concentration at this blood glucose level was unexpectedly variable, ranging from one part-per-million (ppm) to 21 ppm, in contrast to what was previously believed, i.e. that type 1 diabetes mellitus (T1DM) is characterised by high acetone levels. In all 8 patients, the breath acetone declined linearly with blood glucose concentration.

The technique of indirect calorimetry is now widely used to examine rates of energy production and substrate oxidation in humans. Although the basic principles of indirect calorimetry are well established, it is important to recognize that there are several potential pitfalls in the methodology and data interpretation that must be appreciated to properly understand and apply the results derived from this technique. In particular, one must recognize that the fundamental measurement provided by indirect calorimetry is the net disappearance rate of a substrate regardless of the metabolic interconversions that the substrate may undergo before its disappearance from its metabolic pool. Under most circumstances, direct oxidation represents the major route by which a substrate disappears from its metabolic pool, and the two terms are often used interchangeably. However, under conditions when rates of gluconeogenesis, ketogenesis, or lipogenesis are elevated, the presumed equivalence between oxidation and disappearance may no longer apply, even though the actual measurements derived from indirect calorimetry remain valid. When indirect calorimetry is combined with other in vivo metabolic techniques (e.g., the insulin clamp or radioisotope turnover methods) it can provide a powerful tool for noninvasively examining complex metabolic processes.

Clinical indexes of insulin resistance (IR) have acquired increasing importance with the development of various drugs that improve endogenous insulin action (1). Recently, the largest database on insulin clamp studies has been established. This database includes 2,321 subjects, of whom 2,138 are nondiabetic (92%), from 19 sites worldwide (2). Using classification trees, three models have been derived. Model 1 is based on homeostasis model assessment of insulin resistance (HOMA-IR) >4.65, BMI >28.9 kg/m2, or HOMA-IR >3.60 and BMI >27.5 kg/m2. Model 2 is based on BMI >28.7 kg/m2, …

In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone-releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 micrograms/kg i.v. GRF 1-40 was administered to nine poorly controlled IDDM subjects (HbA1 greater than 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (approximately 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 +/- 90 pM) and hyperglycemia (16.5 +/- 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 +/- 11 vs. 20 +/- 4 micrograms/L without insulin infusion, P less than 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 +/- 7 micrograms/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 +/- 84 pM) and hyperglycemia (16.41 +/- 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.

It has been well documented that glucose intolerance is associated with aging, but it is not yet clear whether this phenomenon is due to the aging process itself or is secondary to the appearance of other age-related conditions among which physical inactivity is one of most important variables. To evaluate the effect of aging process and/or physical inactivity on insulin action, this study was undertaken using the euglycemic insulin clamp technique and the oral glucose tolerance test (OGTT). Subjects without diabetes mellitus and other serious diseases consisted of 14 non-obese aged individuals and 10 young controls (YC group), ranging in age from 63 to 85 yrs, and from 19 to 21 yrs, respectively. The aged individuals were further divided into two groups (one was termed as the AS group, in which 7 aged subjects had been confined to bed for at least 3 months and the other was termed as the AC group in which 7 aged controls kept their daily physical activity such as walking). The results of OGTT did not show any remarkable differences between AC and YC groups. In the AS group, however, glucose intolerance and low insulin response during OGTT were observed. In view of the tissue insulin action, MCR, which is thought as a reliable marker for tissue insulin action, evaluated by euglycemic insulin clamp was 5.31 +/- 0.68, 8.57 +/- 1.20, 9.60 +/- 0.35 ml/kg/min in the AS, AC and YC groups, respectively (AS less than AC, p less than 0.05, AS less than YC, p less than 0.01, AC less than YCM, N.S.).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE—To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS—A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18–70 years, BMI 20–65 kg/m2) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. RESULTS—The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose0–30[AUC] × insulin0–30[AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin × basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt ÷ I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). CONCLUSIONS—Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.

This study examined insulin sensitivity at each Tanner (T) stage of puberty in normal children to determine the natural history of insulin resistance in this age group. Participants were randomly selected from a cohort of 12,024 5th-8th grade public school students. Data represent cross-sectional evaluation of the first 318 participants (172 boys, 146 girls). Insulin sensitivity (M, mg/kg/min) was determined by the euglycemic insulin clamp method in which insulin was infused at a rate of 1mU/kg/min for 3h. A variable infusion of 20% dextrose maintained the serum glucose level at 100 mg/dl. At all T stages, M was lower in girls than boys. Insulin sensitivity decreased through the early stages of puberty in both sexes and improved after T3 in girls while remaining relatively constant after T3 in boys. BMI was inversely proportional to M, and was the strongest predictor of M at all T stages in both sexes. For a given BMI, however, M was greater in T5 than T1 in both girls and boys, probably reflecting increased muscle mass with maturity.

The insulin clamp technique, which is often assumed to measure the ability of insulin to stimulate glucose uptake, actually measures both insulin-independent and insulin-dependent glucose uptake. In contrast, the minimal model technique, recently introduced by Bergman, Philips and Cobelli (1981), attempts to directly estimate insulin sensitivity (insulin-dependent glucose uptake = S1) by measurement of plasma glucose and insulin values during a 3 hour intravenous glucose tolerance test (IVGTT). In the present study estimates of insulin action derived from the insulin clamp and the minimal model technique were compared in 20 humans with varying degrees of glucose tolerance. The insulin response during the IVGTT was too low to permit calculation of S1 in 5 subjects - 4 with Type II diabetes and 1 with normal glucose tolerance. Although the correlation coefficient between the two tests in the other 15 patients was statistically significant (r = 0.53, P less than 0.05), this statement is somewhat misleading. Thus, S1 in the 4/7 patients with Type II diabetes in whom it could be measured was zero, and the correlation between estimates of insulin action with the two techniques in the 11 non-diabetic patients was not statistically significant (r = 0.41, P = NS) when these 4 patients were removed from the analysis. In conclusion, these data indicate that there was only a weak correlation between estimates of insulin action assessed with the insulin clamp and the minimal model techniques. One explanation for this observation is that the insulin-independent component of total glucose disposal both varies widely among patients and contributes significantly to glucose uptake as assessed by the insulin clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)

The insulin-stimulated glucose metabolic clearance rate, assessed by the insulin clamp technique, was compared in 40 normal subjects and 40 age- and weight-matched patients with noninsulin-dependent diabetes mellitus. These studies were conducted at steady-state plasma insulin levels of ~100 μU/ml, and the mean (± standard error of the mean) glucose metabolic clearance rate of patients with noninsulin-dependent diabetes mellitus was 81 ± 9 ml/m 2 per minute, as compared with a value of 235 ±14 ml/m 2 per minute for normal subjects. This difference was highly statistically significant (p

Two insulin clamp studies were performed at different steady-state plasma glucose concentrations in 13 patients with non-insulin-dependent diabetes mellitus (NIDDM). Steady-state plasma insulin concentrations were comparable, with mean +/- SEM levels of 94 +/- 3 and 95 +/- 4 muU/ml being achieved during the two studies. Glucose utilization rate (M) varied directly with plasma glucose concentration in each subject. Thus, the mean +/- SEM value of M was 4.92 +/- 0.73 mg/kg/min when patients were studied at a mean +/- SEM plasma glucose concentration of 226 +/- 15 mg/dl, and M was 2.71 mg/kg/min when the same subjects were studied at a glucose concentration of 118 +/- 6 mg/dl. In contrast, the values for glucose metabolic clearance rate (MCR), which were 2.35 +/- 0.50 and 2.49 +/- 0.47 ml/kg/min, respectively, during the two studies, did not vary significantly with plasma glucose concentration. These data indicate that the glucose metabolic clearance rate (MCR), but not glucose utilization rate (M), can be used to compare in vivo insulin action when insulin clamp studies are performed in subjects with different basal plasma glucose concentrations.

Smoking increases counterregulatory hormone secretion and reduces capillary flow, both of which could reduce insulin mediated glucose disposal. To evaluate whether smoking has any effect on body sensitivity to insulin, we measured insulin-mediated glucose disposal (1 mU euglycemic insulin clamp) during acute smoking in seven male type I diabetic patients. In addition, we performed a cross-sectional study to compare insulin sensitivity in 12 habitually smoking and 22 nonsmoking diabetic patients matched for age, relative body weight, sex, diabetes duration, HbA1, C-peptide, and insulin dose. In the acute study, baseline counterregulatory hormone levels were comparable in the smoking and control experiment. During smoking (9 to 12 cigarettes), carboxyhemoglobin level rose by 57% (P less than 0.01). Circulating adrenaline, cortisol, growth hormone, and glucagon levels were 40% to 100% higher during smoking than during the control clamp study (P less than 0.05-0.01). During acute smoking the rate of insulin-mediated glucose uptake (7.3 +/- 1.0 mg/kg/min) was not significantly different from that without cigarettes (6.8 +/- 0.7 mg/kg/min). In the cross-sectional study, the rate of glucose uptake was comparable in habitually smoking (5.0 +/- 0.5 mg/kg/min) and nonsmoking patients (4.8 +/- 0.3 mg/kg/min). Thus, inspite of a significant rise in counterregulatory hormones, neither acute nor habitual smoking causes substantial changes in insulin sensitivity in type I diabetics.

To evaluate the role of abnormal glucagon physiology in the glucose intolerance of aging, we have examined: (1) basal glucagon concentration, (2) suppression of plasma glucagon by hyperglycaemia and hyperinsulinaemia, (3) plasma glucagon response to intravenous alanine, (4) glucagon kinetics, and (5) hepatic sensitivity to glucagon (3 ng·kg-1·min-1 for 3 h) using 3-3H-glucose in young (24±1 years), middleaged (41±2 years), and older (62±2 years) subjects. Fasting plasma glucagon levels in 58 young, 21 middle-aged, and 32 older subjects were 89±10, 91±12, and 96±21 pg/ml, respectively (p=NS). Following elevation of plasma glucose to 2.2–6.9 mmol/l above basal for 2 h (hyperglycaemic clamp technique), young, middle-aged, and older subjects showed similar depressions in plasma glucagon levels during all three studies. Elevation of the plasma insulin concentration to approximately 100 mU/l while maintaining euglycaemia (insulin clamp technique) also resulted in a similar decline in plasma glucagon levels in both young and older subjects (by 25±3 and 27±3 pg/ml respectively). Following intravenous alanine infusion, the increase in plasma glucagon was not significantly different in young compared with older subjects (65±16 versus 38±7 pg/ml). Plasma insulin (7±1 versus 8±1 mU/l) and glucose (0.33±0.11 versus 0.50±0.11 mmol/l) responses were comparable in young and older subjects. During continuous glucagon infusion, the steady-state plasma glucagon concentration (267±32 versus 252±12 pg/ml) and the metabolic clearance rate of glucagon (16±1 versus 15±1 ml· kg-1·min-1) were similar in young and older subjects. However, the increase in plasma glucose concentration was significantly greater in the older than young subjects (Δ=1.17±0.11 versus 0.67±0.06 mmol/l, p

This study was initiated to compare the abilities of two alternative approaches to the measurement of insulin-dependent glucose disposal in normal humans. The ability of insulin to stimulate glucose disposal was measured in 12 normal subjects by determining glucose disposal rates during insulin clamp studies carried out at both basal insulin concentrations (approximately 6 microU/ml) and during a period of sustained hyperinsulinemia (approximately 60 microU/ml). The increment in glucose disposal was defined as insulin-dependent disposal and compared to estimates of insulin action generated by both the conventional insulin clamp approach and the minimal model technique. The results documented an extremely close correlation (r = 0.99; P less than 0.001) between the direct determination of insulin-dependent glucose disposal and insulin-stimulated glucose disposal as estimated by the insulin clamp technique. In contrast, there was a poor correlation (r = 0.44; P = NS) between insulin sensitivity as estimated by the minimal model technique and insulin-dependent glucose disposal. These results indicate that the value of glucose disposal determined by the insulin clamp approach, which includes both insulin-independent and insulin-dependent glucose disposal, provides an excellent estimate of insulin-dependent glucose disposal in subjects with normal glucose tolerance. Unfortunately, this does not appear to be true of the minimal model technique. However, it must be emphasized that these conclusions are only applicable to normal humans, and may not apply to normal subjects of other species or to humans under different physiological or pathological situations.

Tissue sensitivity to insulin was evaluated in 6 trained athletes and 9 untrained controls using the euglycemic insulin clamp technique. The amount of glucose metabolism is a measure of overall tissue sensitivity to insulin. During insulin clamp study comparable plasma glucose (80-90 mg/dl) and insulin (90-100 microU/ml) were achieved in both groups. The glucose infusion rate in the athletes (10.70 +/- 0.32 mg/kg/min) was significantly higher than in the controls (7.37 +/- 0.23 mg/kg/min). During euglycemic hyperinsulinemia plasma FFA decreased by 80% while glycerol showed only a 20% reduction in both groups. Urinary catecholamine concentrations in the athletes were similar to those in the controls, and these levels did not change during the insulin clamp period. From these results, it might be concluded that tissue sensitivity to exogenous insulin is 45% higher in trained athletes and that physical exercise can reduce the insulin requirements in insulin-dependent diabetic patients in addition to being beneficial to noninsulin-dependent diabetics.