Glucose effectiveness is a critical pathogenic factor leading to glucose intolerance and type 2 diabetes: An ignored hypothesis.

BACKGROUND: Although the ability of glucose to mediate its own in vivo metabolism is long documented, the quantitative measurement of whole body glucose-mediated glucose disposal at basal insulin levels (glucose effectiveness [GE]), followed the introduction of the Minimal Model intravenous glucose tolerance test technique. METHODS: A literature review, combined with our own studies, of the role of GE in glucose metabolism in normal and "at risk" individuals, was undertaken to determine GE's contribution to glucose homeostasis. RESULTS: GE accounts for ~45% to 65% of glucose disposal in man. A negative association between GE and insulin meditated glucose disposal (Si), is present in normal subjects without a family history of type 2 diabetes mellitus but is absent in normoglycaemic "at risk" relatives with a positive family history of diabetes mellitus. Intracellular GE disposal is mediated by mass action of glucose through the skeletal muscle membrane via facilitated Glut 4 transporters. However, GE is frequently forgotten as a significant contributor to the development of glucose intolerance in "at risk" individuals. Only limited studies have examined the role of a lower GE in such normoglycemic subjects with preexisting mild insulin resistance and ß-cell dysfunction. These studies demonstrate that in "at risk" individuals, an initial low GE is a key contributor and predictor of future glucose intolerance, whereas an initial raised GE is protective against future glucose intolerance. CONCLUSION: In "at risk" individuals, a low GE and genetically determined vulnerable ß-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.

Glucose effectiveness in nondiabetic relatives: dysglycemia and ß-cell function at 10 years.

AIMS: Reduced glucose effectiveness is a predictor of future glucose tolerance in individuals with a family history of type 2 diabetes. We examined retrospectively at 10 years in normoglycemic relatives of diabetic subjects (RELs) the pathophysiological role of glucose effectiveness in the development of isolated impaired fasting glucose, glucose intolerance, and acute insulin release. METHODS: At 0 years, 19 RELs and 18 matched control subjects had glucose effectiveness (GE), insulin sensitivity, acute insulin release (AIR)IVGTT, and disposition index measured during an iv glucose tolerance test (IVGTT), using the minimal model analysis. At 0 and 10 years, oral glucose tolerance (OGTT) and AIROGTT were determined. RESULTS: At 0 years, fasting glucose (FG) and GE were raised in RELs, but insulin sensitivity and AIROGTT were reduced (P ≤ .05) compared with controls. At 10 years, RELs developed raised fasting and 2-hour OGTT glucose. FG10y correlated significantly with FG0y and body mass index0y and negatively with √GE and 2-hour OGTT glucose10y with FG0y and negatively with AIRIVGTT0y and AIROGTT0y. Log AIROGTT10y correlated with √GE, log AIRIVGTT0y and log AIROGTT0y. Multiple regression analyses demonstrated the following: REL FG10y was predicted by combined FG0y, √GE and body mass index0y (radj(2) = 56%; P ≤ .001) and 2-hour OGTT glucose10y weakly related by FG0y,and √GE (r(adj)(2) = 25%; P = .06). Log AIROGTT10y was predicted by AIRIVGTT0y and √GE (r(adj)(2) = 46%; P ≤ .004). CONCLUSION: In normoglycemic RELs, a relative reduction of glucose effectiveness is an important contributor over 10 years to the development of isolated impaired fasting glucose and reduced acute insulin secretion.

Skeletal muscle 11ßHSD1 activity of nondiabetic subjects is unaltered in central obesity-associated insulin resistance.

Local activation of glucocorticoids in insulin target tissues by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) has been implicated in the etiology of the metabolic syndrome. In obesity, adipose tissue 11ßHSD1 is upregulated, leading to the generation of higher tissue levels of cortisol, which may increase insulin resistance. However, skeletal muscle is the predominant site of insulin-mediated glucose disposal, which is known to be reduced in obesity. We aimed to determine if there is any relationship between skeletal muscle 11ßHSD1 and markers of central adiposity and insulin resistance in nondiabetic subjects. 20 nondiabetic volunteers (8 males and 12 females, mean age 55 ± 13 years, body mass index 21.5-47.6, mean 30.4 ± 1.6 kg/m (2)) underwent a single fasting blood sample followed by a muscle biopsy of vastus lateralis under local anesthetic. Fasting glucose, insulin and adiponectin were measured in serum. Skeletal muscle 11ßHSD1 oxoreductase activity was determined by measuring the conversion of radiolabelled (3)H-cortisone to cortisol by thin layer chromatography. When subjects were categorised according to abdominal obesity (waist circumference ≥ 102 cm in men, ≥ 88 cm in women), there was no difference between the groups in skeletal muscle 11ßHSD1 activity. There was no correlation between body mass index or waist circumference and 11ßHSD1 activity or between HOMA and 11ßHSD1 activity. Skeletal muscle 11ßHSD1 oxoreductase activity is not altered in nondiabetic subjects with central obesity-associated insulin resistance. It is therefore unlikely that the in vivo insulin resistance observed in skeletal muscle of centrally obese subjects is mediated by alterations in 11ßHSD1.

Contrasting effects of exercise, AICAR, and increased fatty acid supply on in vivo and skeletal muscle glucose metabolism.

The increased energy required for acute moderate exercise by skeletal muscle (SkM) is derived equally from enhanced fatty acid (FA) oxidation and glucose oxidation. Availability of FA also influences contracting SkM metabolic responses. Whole body glucose turnover and SkM glucose metabolic responses were determined in paired dog studies during 1) a 30-min moderate exercise (maximal oxygen consumption of approximately 60%) test vs. a 60-min low-dose 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion, 2) a 150-min AICAR infusion vs. modest elevation of FA induced by a 150-min combined intralipid-heparin (IL/hep) infusion, and 3) an acute exercise test performed with vs. without IL/hep. The exercise responses differed from those observed with AICAR: plasma FA and glycerol rose sharply with exercise, whereas FA fell and glycerol was unchanged with AICAR; glucose turnover and glycolytic flux doubled with exercise but rose only by 50% with AICAR; SkM glucose-6-phosphate rose and glycogen content decreased with exercise, whereas no changes occurred with AICAR. The metabolic responses to AICAR vs. IL/hep differed: glycolytic flux was stimulated by AICAR but suppressed by IL/hep, and no changes in glucose turnover occurred with IL/hep. Glucose turnover responses to exercise were similar in the IL/hep and non-IL/hep, but SkM lactate and glycogen concentrations rose with IL/hep vs. that shown with exercise alone. In conclusion, the metabolic responses to acute exercise are not mimicked by a single dose of AICAR or altered by short-term enhancement of fatty acid supply.

The relationship between peripheral glucose utilisation and insulin sensitivity in the regulation of hepatic glucose production: studies in normal and alloxan-diabetic dogs.

BACKGROUND: Hepatic glucose overproduction (HGP) of diabetes could be primary or could occur in response to the metabolic needs of peripheral (skeletal muscle (SkM)) tissues. This question was tested in normal and diabetic dogs. METHODS: HGP, SkM glucose uptake (Rd(tissue)), metabolic clearance of glucose (MCRg) and glycolytic flux (GF(exog)), and SkM biopsies were measured in the same dogs before and after alloxan-induced diabetes. Normal dogs were exposed to (1) an extended 20-h fast, (2) low- and high-dose glucose infusions (GINF) at basal insulinaemia, and chronic diabetic dogs were exposed to (3) hyperglycaemia, (4) phlorizin-induced normoglycaemia, and (5) poor and good diabetic control. RESULTS: (1) Prolonged fast: HGP, Rd(tissue), and GF(exog) fell in parallel (p < 0.05). (2) Low-dose GINF: plasma glucose, insulin, Rd(tissue), MCRg, and GF(exog) were unchanged, but HGP fell by approximately 40%, paralleling the supplemental GINF. (3) High-dose GINF at basal insulin: plasma glucose doubled and synchronous changes in HGP, Rd(tissue), MCRg, and GF(exog) occurred; IC(glucose), G6P, and glycogen were unchanged. (4) Hyperglycaemic diabetes: HGP was raised (p < 0.05), matching urinary glucose loss (UGL) and decreased MCR(g), and maintaining normal basal Rd(tissue) and GF(exog). SkM IC(glucose) was increased and glycogen decreased (both p < 0.05). (5) Phlorizin-induced normoglycaemia in diabetic dogs: HGP rose, matching the increased UGL, while maintaining normal Rd(tissue) and GF(exog). Intramuscular substrates normalised. (6) Whole body and SkM metabolism normalised with correction of the insulin resistance and good diabetic control. CONCLUSION: HGP reflects whether SkM is in a state of relative glucose 'excess' or absolute/relative glucose 'deprivation'.

Impaired non-esterified fatty acid suppression to intravenous glucose during late pregnancy persists postpartum in gestational diabetes: a dominant role for decreased insulin secretion rather than insulin resistance.

AIMS/HYPOTHESIS: Non-esterified fatty acids are implicated in the pathogenesis of gestational (GDM) and type 2 diabetes. We examined the relationship between NEFA dynamics, insulin resistance and beta cell dysfunction in women with GDM in late pregnancy and postpartum. METHODS: A total of 19 Caucasian women with GDM and 19 healthy pregnant women matched for BMI and age underwent an IVGTT in the third trimester and 4 months postpartum, deriving values for insulin sensitivity (SI), insulin secretion (AIRg) and disposition index (DI). NEFA levels were measured serially. RESULTS: In pregnancy, the GDM women had similar SI but reduced AIRg and DI compared with control subjects. The GDM group demonstrated significantly slower NEFA suppression, which was attributable to the GDM women who required insulin during pregnancy (n=7) and who had markedly reduced AIRg and K(NEFA) (NEFA disappearance constant) compared with their matched controls. In contrast, GDM subjects not requiring insulin (n=12) had similar NEFA suppression curves and AIRg to control subjects. Postpartum, GDM subjects demonstrated reduced SI and DI. The impaired suppression of NEFA persisted postpartum, but again only in the subgroup of GDM subjects who had required insulin during pregnancy. Furthermore, K(NEFA) correlated with AIRg and DI in both states, but not with SI. CONCLUSIONS/INTERPRETATION: Impaired NEFA suppression occurs in GDM subjects both in late pregnancy and postpartum in response to IVGTT-induced endogenous insulin secretion. The impaired NEFA suppression is present in GDM women with the most severe beta cell dysfunction (who had required insulin during pregnancy) and is related to their insulin secretory dysfunction rather than their reduced SI.

The impact of acute elevation of non-esterified fatty acids on insulin sensitivity and secretion in women with former gestational diabetes.

OBJECTIVES: Elevations in non-esterified fatty acids (NEFA) have been shown to decrease insulin action and secretion, and are a risk factor for the development of Type 2 diabetes. As women who have had gestational diabetes (GDM) are at increased risk of diabetes, we examined the effect of an acute elevation of NEFA on insulin secretion and action in these women. PATIENTS AND DESIGN: Nineteen women with recent former GDM and 19 age- and BMI-matched postpartum healthy control subjects underwent a 40-min intravenous glucose tolerance test, with and without a preceding 2-h infusion of 20% Intralipid. Insulin action was assessed by glucose disappearance (Kg) and insulin sensitivity (SI); insulin secretion by first phase insulin release (FPIR) and disposition index (DI). RESULTS: NEFA levels were similarly elevated in both groups by the Intralipid infusion (up to 1.140 +/- 0.03 mm). As expected, the lipid infusion significantly reduced Kg (2.15 +/- 0.13 vs. 1.69 +/- 0.09/min, P < 0.001) and SI (3.14 +/- 0.28 vs. 2.13 +/- 0.17/min/mUl/min, P < 0.001) in all subjects, and these were significant within the GDM and control subgroups. FPIR was elevated in the Intralipid study in the total group of women (4.50 +/- 0.50 vs. 5.02 +/- 0.53, P = 0.02), but DI was significantly reduced (12.13 +/- 1.1 vs. 8.83 +/- 0.7, P < 0.001). There was no significant difference, however, in the absolute or percentage change in Kg, SI or FPIR with lipid infusion between the GDM and control groups. GDM status was not a predictor of the response of Kg, SI or FPIR to lipid infusion, rather, adiposity (% fat), average fasting NEFA levels and basal disposition index were associated. CONCLUSION: These data suggest that women with former gestational diabetes, in contrast to other prediabetic states, are not more susceptible to the deleterious effects of an acute elevation in nonesterified fatty acids than matched control subjects.

Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes.

AIMS/HYPOTHESIS: Insulin resistance of skeletal muscle has been associated with increased lipid availability. This study aimed to estimate volume fractions of intramyocellular triglyceride droplets and glycogen granules in skeletal muscle using electron microscopy and furthermore, relate these findings to insulin sensitivity and the level of circulating lipids. METHODS: We compared 11 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 11 obese normoglycaemic subjects matched for age and sex. Glucose metabolism was determined using the euglycaemic hyperinsulinaemic clamp technique (40 mU.m(-2).min(-1)) coupled with indirect calorimetry and tritiated glucose. On the second day, using an automatic procedure, a fasting muscle biopsy was carried out and processed for electron microscopy. Volume fractions of intramyocellular structures were estimated by pointcounting on photographic pictures in a blinded manner. RESULTS: Insulin-stimulated total glucose disposal rate was lower in the Type II diabetic subjects compared with the obese normoglycaemic subjects (4.96 +/- 049 vs 10.35 +/- 0.89 mg.min(-1).kg ffm(-1), p < 0.001) as was glucose storage (2.03 +/- 0.50 vs 6.59 +/- 0.83, p < 0.001). The electron microscopy study revealed that the diabetic subjects had higher intramyocellular amounts of triglyceride (1.43 +/- 0.21 vs 0.39 +/- 0.07%, p < 0.001) and lower amounts of glycogen (3.53 +/- 0.33 vs 6.94 +/- 0.54%, p < 0.001). Mitochondrial volume was identical indicating equal aerobic capacity. The fractional intramyocellular lipid volume was found to be positively associated with fasting NEFA (r = 0.63, p = < 0.05 and r = 0.79, p = < 0.05) and triglyceride (r = 0.74, p = 0.01 and r = 0.62, p < 0.05) in the obese diabetic and normoglycaemic cohorts respectively. Intramyocellular lipid content was negatively correlated to insulin sensitivity (r = -0.71, p < 0.02) in the obese diabetic group whereas no significant association was found in the obese normoglycaemic group. CONCLUSION/INTERPRETATION: This study shows that fat accumulates intramyocellulary while glycogen stores are simultaneously reduced in obese subjects with Type II (non-insulin-dependent) diabetes mellitus. Quantitatively, a major component of the excessive lipid accumulation could be secondary in origin, related to the diabetic state in itself, although a contribution from the altered insulin action cascade of obesity and diabetes cannot be excluded. In both groups significant positive relations were found between circulating and intramyocellular lipid.

Physiologic modeling of the intravenous glucose tolerance test in type 2 diabetes: a new approach to the insulin compartment.

The minimal model of Bergman et al has been used to yield estimates of insulin sensitivity (Si) and glucose effectiveness (Sg) in type 2 diabetes by incorporating exogenous insulin protocols into the regular intravenous glucose tolerance test (IVGTT). These estimates, however, are influenced by the degree to which the dose of exogenous insulin is greater than the physiologic response to a glucose load. Moreover, most studies have related to type 2 diabetes subjects whose diabetes was relatively mild in terms of therapeutic requirements. To develop a "minimal disturbance" approach in estimating Si and Sg in type 2 diabetes, we have used a reduced glucose load (200 mg/kg) and a "physiologic" insulin infusion throughout the IVGTT in a series of 8 patients, 5 of whom were insulin-requiring. Data from this approach were analyzed using the modelling program CONSAM to apply the Bergman model, either unmodified (BMM), or incorporating an additional delay element between the plasma and "remote" insulin compartments (MMD). Application of the MMD and extension of the IVGTT from 3 to 5 hours improved successful resolution of Si and Sg from 37.5% (BMM, 3-hour IVGTT) to 100% (MMD, 5-hour IVGTT). Si was reduced in these type 2 diabetes patients compared with normal subjects (1.86 +/- 0.60 v. 8.65 +/- 2.27 min(-1) x microU(-1) x mL x 10(4) P <.01). The results were validated in the type 2 diabetes group using a 2-stage euglycemic clamp ((Si)CLAMP = 2.02 +/- 0.42 min(-1) x microU(-1) x mL x 10(4) P >.4). Sg was not significantly reduced (2.00 +/- 0.25 type 2 diabetes v. 1.55 +/- 0.26 normal min(-1) x 10(2)). Data from a group of normal nondiabetic subjects was then analyzed using the MMD, but this approach did not enhance the fit of the model compared with the BMM. This result indicates that the delay in insulin action in type 2 diabetes represents an abnormality whereby the onset of insulin action cannot be described as a single phase in the transfer of insulin from plasma to the remote compartment. It is postulated that the physiologic basis for this delayed action may relate to transcapillary endothelial transfer of insulin, this process limiting the rate of onset of insulin action.

Insulin sensitivity in growth hormone (GH)-deficient adults and effect of GH replacement therapy.

Growth hormone (GH) deficiency in adults is characterized by central obesity, dyslipidemia, coagulopathy and glucose intolerance, all features of the "metabolic syndrome", explaining the increased cardiovascular morbidity and mortality associated with GH deficiency in adults. Employing the 2-step euglycemic-hyperinsulinemic clamp, we have demonstrated severe insulin resistance in GH-deficient adults, with a reduction in insulin-mediated glucose utilization of -50%. Basal glucose turnover and partitioning of whole body glucose utilization into glycolytic flux (GF) and glycogen synthesis/glucose storage (GS) pathways are normal, but insulin activation of these 2 pathways is reduced, predominantly in the GS pathway. Activation of muscle glycogen synthase by insulin is markedly decreased, as is glycogen content of muscle. Insulin-induced muscle hexokinase activity appears also to be attenuated in GH-deficient adults with raised intramuscular cellular glucose and normal-reduced concentrations of glucose-6-phosphate. Beta-cell function is not excessive in GH-deficient adults and is inappropriately low for the insulin resistance. Following treatment of GH-deficient adults with recombinant GH (rhGH), the insulin resistance is either unchanged or more pronounced by 3, 6 or 24 months of treatment, despite the significant reduction in general and central obesity. The GF and GS pathways and muscle glycogen synthase and hexokinase activities remain severely impaired. Abnormalities in free fatty acid (FFA) metabolism are present in rhGH-treated GH-deficient adults and correlate significantly with the degree of insulin resistance as do the concentrations of rhGH-induced insulin-like growth factor (IGF)-I, the post-basal insulinemia and the duration of the GHD, but is independent of obesity. In conclusion, long-term rhGH treatment in GH-deficient adults results in persistent insulin resistance and abnormalities in the GF and GS pathways due to reduced glycogen synthase and hexokinase activities, in the presence of an ongoing reduction of central obesity. We postulate that the insulin resistance is due to chronic rhGH-induced alterations in FFA metabolism, non-physiological levels of IGF-I and chronic basal hyperinsulinemia.

The Melbourne Pre-Diabetes Study: prediction of type 1 diabetes mellitus using antibody and metabolic testing.

OBJECTIVES: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus. PARTICIPANTS: 3315 first-degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. MAIN OUTCOME MEASURES: Prevalence of islet cell antibodies (ICA) levels > or = 20 JDFu, insulin autoantibodies (IAA) levels > 100 nU/mL, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in beta cell function over time; and development of clinical diabetes. RESULTS: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50 mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50 mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. CONCLUSIONS: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.

Impact of family history of diabetes on the assessment of beta-cell function.

Numerous factors impinge on beta-cell function, and include the genetic background and insulin sensitivity of the individual. The aim of the present study was to evaluate the impact of a family history of non-insulin-dependent diabetes mellitus (NIDDM) on beta-cell function and to determine whether the relationships between beta-cell function and insulin sensitivity and age are influenced by a family history of diabetes. Thirty-three healthy control subjects (CON), 20 normal glucose-tolerant first-degree relatives of known NIDDM patients (REL), and 12 nondiabetic identical twins with an identical twin with known NIDDM were studied. Insulin and C-peptide responses to an acute intravenous glucose (AIRg) and glucagon bolus (at euglycemia [AIR[G.GON]]) were measured, as well as each individual's insulin sensitivity. Fasting insulin and C-peptide levels were similar in all groups. AIRg was significantly reduced by 65% in the nondiabetic twins compared with the CON and REL groups, with the latter group being similar to CON, whereas for the AIR[G.GON], the insulin responses in the twin subjects were reduced only by 35% compared with CON. Following stepwise (default) multiple regression analysis, three independent variables (insulin sensitivity, 23%; family history of NIDDM, 20%; and fasting glucose, 7%) were identified, and these combined to fit a model for prediction of acute beta-cell responses to glucose that yielded an R2 (adjusted) value of 50%. Following analysis of covariance (ANCOVA), a positive family history of NIDDM and insulin sensitivity but not the age of the subject were confirmed as separate factors affecting AIRg. In conclusion, in subjects with normal or mild glucose intolerance, the individual's genetic background and insulin sensitivity are important determinants of insulin secretion.

Growth hormone deficiency and cardiovascular risk.

It is now recognized that growth hormone (GH) deficiency in adults represents a distinct clinical syndrome that encompasses reduced psychological well-being as well as specific metabolic abnormalities. The latter features, which include hypertension, central obesity, insulin resistance, dyslipidaemia and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes. Replacement of GH in GHD adults has resulted in a marked reduction of central obesity and significant reduction in total cholesterol but little change in other risk factors, in particular insulin resistance and dyslipidaemia. The persistent insulin resistance and dyslipidaemia, together with the elevation of plasma insulin levels and lipoprotein (a) with GH replacement in these subjects are of concern. Long-term follow-up data are required to assess the impact of GH replacement on the cardiovascular morbidity and mortality of GHD adults. Further exploration of the appropriateness of the GH dosage regimens currently being employed is also indicated.

The effect of norepinephrine on insulin secretion and glucose effectiveness in non-insulin-dependent diabetes.

It has previously been shown that in normal subjects, physiological elevation of norepinephrine (NE) impairs insulin sensitivity (Si) but does not influence insulin secretion. The aim of this study was to determine the effect of short-term physiological elevation of NE on insulin secretion, Si, and glucose-mediated glucose disposal, or the glucose effectiveness index (Sg), in non-insulin-dependent diabetes mellitus (NIDDM). Two intravenous glucose tolerance tests (IVGTTs) were performed in eight well-controlled NIDDM patients, using a supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. The IVGTTs were performed in random order after 30 minutes of either the saline (SAL) or NE (25 ng/kg/min) infusions, which were continued throughout the 3-hour IVGTT. Sg and Si were estimated by minimal model analysis of the IVGTT data as previously described. Plasma C-peptide was used to estimate insulin secretion rate using the ISEC program. NE infusion produced approximately a threefold increase in plasma NE, associated with (1) a significant reduction in glucose disposal ([KG] SAL v NE, 0.73 +/- 0.06 v 0.61 +/- 0.06 x 10(-2).min-1, P < .05), (2) no reduction in Si (2.33 +/- 0.8 v 2.62 +/- 0.9 x 10(-4).min-1/mU/L, NS), (3) a reduced mean second-phase insulin secretion rate (1.21 +/- 0.19 v 1.01 +/- 0.16 x 10(-3) pmol/kg/min per mmol/L glucose, P < .05), (4) a significant increase in Sg (0.89 +/- 0.08 v 1.63 +/- 0.2 x 10(-2).min-1, P < .05), and (5) a corresponding increase in glucose effectiveness at zero insulin ([GEZI] 0.55 +/- 0.13 v 1.30 +/- 0.33 x 10(-2).min-1, P < .05). These results show that in contrast to normal subjects, physiological elevation of NE in NIDDM does not result in a reduction in Si, but causes a reduction in glucose disposal related to inhibition of insulin secretion that is only partially compensated for by increased Sg.

Reproducibility of the first-phase insulin response to intravenous glucose is not improved by retrograde cannulation and arterialization or the use of a lower glucose dose.

OBJECTIVE: To determine whether the reproducibility of the first-phase insulin response (FPIR) measured during an intravenous glucose tolerance test is improved by the use of a lower glucose dose or retrograde sampling from an arterialized hand vein. RESEARCH DESIGN AND METHODS: Previous studies have suggested that the high within-subject variation of FPIR measurement of up to 110% could be reduced by sampling from a retrograde cannulated and arterialized hand vein opposite to the cubital fossa vein through which the glucose was injected or by the use of a lower dose of glucose. Two low-dose (glucose, 5 g/m2 injected over 30 s) and two standard Islet Cell Antibody Registry Users Study (ICARUS) (glucose, 0.5 g/kg injected over 3 min) tests were performed on seven normal subjects at 2-week intervals. Samples were collected simultaneously from the cubital fossa vein, through which the glucose was injected, and from a retrograde cannulated, contralateral hand vein that was arterialized by heating. FPIR was expressed as the sum of the insulin measurements 1 and 3 min after the completion of the glucose injection and as the area under the insulin curve between 0 and 10 min. RESULTS: Responses to the mean sum of serum insulin concentrations at 1 and 3 min after intravenous glucose were significantly lower for the low-dose test (mean 94 mU/l) than for the high-dose test (mean 184 mU/l) for samples taken from the arm (P < 0.05); mean 0- to 10-min insulin areas were 367 and 596 mU/l for low- and high-dose tests, respectively (P < 0.05). Within-subject coefficients of variation for samples from the hand or the arm ranged from 0.33 to 17.5% and 1.3 to 38% for successive ICARUS and low-dose tests, respectively. Reproducibility, measured by the coefficient of variation between successive tests for each protocol, was not significantly different using samples taken from the arm or the contralateral hand. CONCLUSIONS: The intravenous glucose tolerance test is reproducible when performed by the same operator over a short time span. Reproducibility is not significantly improved by sampling from an arterialized, retrograde cannulated, contralateral hand vein. There is no case for changing the present ICARUS protocol to incorporate retrograde cannulation or low-dose (5 g/m2) glucose.

Insulinopenia and hyperglycemia influence the in vivo partitioning of GE and SI.

We determined the impact of variable insulinemia and glycemia on the in vivo partitioning of glucose effectiveness (GE) and insulin sensitivity (SI) and the in vitro intracellular processing of glucose metabolism. Six somatostatin- and [3-3H]glucose-infused dogs underwent euglycemic and hyperglycemic clamps at four physiological insulin (Ins) levels before a muscle biopsy. From the rates of glucose infusion (GINF), total glucose disposal (Rd), total glycolysis (GF), and glucose storage (GS), plots of delta GINF, delta Rd, delta GS vs. delta log Ins concentration were found to be linear for each dog, allowing calculation of the partitioning of GE and SI into their major in vivo sites (periphery vs. liver) and intracellular metabolic pathways (GS vs. GF). Insulinopenia induced a significant reduction in total GE. From insulinopenia to high insulinemia, the 2.3-fold increase in total GE was due to the increased peripheral glucose responsiveness of the GS pathway. Hyperglycemia induced a significant reduction in total SI, with approximately one-half of this reduction due to the decreased peripheral insulin responsiveness of the GF pathway. In skeletal muscle, both glycogen content and glycogen synthase fractional activity were positively correlated with log Ins concentration, Rd, and GS but negatively correlated with glucose 6-phosphate concentration. Moreover, both Rd and GS were negatively correlated with lactate concentration. We conclude that 1) the inhibition of GE and SI induced by insulinopenia and hyperglycemia, respectively, is due mainly to the reduced peripheral responsiveness of contrasting intracellular metabolic pathways; and 2) hyperinsulinemia and/or hyperglycemia stimulates glycogen synthesis and GF but not nonoxidative glycolysis.

The effect of 3 months of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults: a minimal model analysis.

The effect of 3 months of low dose (120 micrograms/kg.week or 0.24 IU/kg.week) recombinant human GH (rhGH) treatment on glucose tolerance, insulin secretion, and insulin- and glucose-mediated glucose disposal was examined in 10 GH-deficient adults. The frequently sampled iv glucose tolerance test was performed at baseline and after 1 week and 3 months of rhGH therapy and analyzed by the minimal model method of Bergman to provide estimates of the glucose decay rate, first and second phase insulin secretion (phi 1 and phi 2), fractional clearance of insulin, and glucose-mediated and insulin-mediated glucose disposal. Fasting glucose, insulin, C-peptide, nonesterified fatty acids (NEFA), and serum cholesterol and triglycerides were also measured. When the 1 week data were compared to baseline, there was a small but significant rise in mean (+/- SE) fasting glucose (4.62 +/- 0.17 vs. 5.1 +/- 0.15 mmol/L; P < 0.01), NEFA (0.70 +/- 0.09 vs. 1.1 +/- 0.12 mmol/L; P < 0.005), insulin (93.6 +/- 8.9 vs. 238.9 +/- 9.2 pmol/L; P < 0.0001), C-peptide (0.32 +/- 0.13 vs. 0.66 +/- 0.13 nmol/L; P < 0.005), and phi 1 (11.9 +/- 1.3 vs. 16.2 +/- 1.8 pmol/L.min/mmol.L x 10(2)) and phi 2 (1.43 +/- 0.17 vs. 3.15 +/- 0.25 pmol/L.min/mmol.L x 10(3); P < 0.05). Conversely, there were associated decreases in glucose decay rate (1.83 +/- 0.26 vs. 1.28 +/- 0.12 min-1; P < 0.05) and insulin-mediated glucose disposal (0.36 +/- 0.08 vs. 0.18 +/- 0.06 min/pmol.L x 10(-4); P < 0.005). There was no change in glucose-mediated glucose disposal or the fractional clearance of insulin. By 3 months, fasting insulin and C-peptide levels remained significantly elevated, whereas other parameters had returned to baseline. There was a minor reduction in serum cholesterol at 1 week (5.1 +/- 0.15 vs. 4.62 +/- 0.17 mmol/L; P < 0.01), which was not maintained at 3 months. Serum triglycerides remained unchanged throughout the study. We conclude that short term low dose rhGH treatment of GH-deficient adults induces a temporary state of mild glucose intolerance, hyperinsulinemia, insulin resistance, and raised NEFA levels at 1 week. By 3 months, these metabolic disturbances had returned to baseline for a persisting modest hyperinsulinemia. Whether this hyperinsulinemia will last over the longer term and/or has distant detrimental metabolic consequences in the individual must await further studies.

Impact of variable insulinemia and glycemia on in vivo glycolysis and glucose storage in dogs.

To determine the impact of variable plasma insulin concentrations and glycemia on the partitioning of whole body glucose metabolism between glycolysis and glucose storage, we estimated endogenous hepatic glucose production and rates of in vivo glycolytic flux (GF) and glucose storage (GS) in six normal dogs from the generation of plasma tritiated water (3H2O) and [3-3H]glucose specific activity during 150 min of somatostatin euglycemic (E) and hyperglycemic (H) clamps at hypoinsulinemic, basal, intermediate, and high insulin levels. During both E and H clamps, overall rates of GF and GS increased with the rising insulin levels, but the relative contributions to in vivo glucose disposal of GF decreased, whereas GS rose progressively with increasing insulin levels. The relative contribution of GS during H to overall glucose disposal was greater at the lower insulin level. In addition, in absolute terms, GF and GS were significantly higher (P < 0.05) during H than during E at all insulin levels. Moreover, the incremental rise in GF induced by H was equal for the low to intermediate insulin levels tested, independent of the prevailing free fatty acid (FFA) levels. However, when whole body glucose disposal rates were matched, GF and GS rates were independent of the coexisting glycemia, insulin, and/or FFA levels. We conclude that 1) insulin has a major impact on the intracellular fate of infused glucose, with a lesser but significant effect of hyperglycemia per se on these processes; 2) the magnitude of the hyperglycemia-induced increase in GF is independent of the prevailing insulin level from low to intermediate levels; and 3) in vivo GF and GS are dependent on the net rate of glucose uptake into cells but independent of absolute FFA levels or whether glucose uptake is stimulated by raised insulin or glucose levels.

Impaired glucose tolerance after endurance exercise is associated with reduced insulin secretion rather than altered insulin sensitivity.

Paired frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on five highly trained athletes within 2 hours of completing a 6-day ultramarathon run (E) and after 2 weeks of complete rest (R). Severe exercise increased free fatty acid (FFA) levels (E 1.2 +/- 0.16 v 0.42 +/- 0.07 mmol/L, P < .01) and norepinephrine levels (E 573 +/- 141 v 224 +/- 33 pg/mL, P < .01), with only moderate reductions in glucose tolerance (glucose disappearance [Kg] E 1.06 +/- 0.2 v R 1.7 +/- 0.3 min-1 x 10(2), P < .05). The minimal model analysis of FSIGT data using the method of Bergman et al (Endocr Rev 6:45-86, 1985) showed a reduced second-phase insulin secretion ([phi 2] E 5.2 +/- 1.3 v 13 +/- 2.2 microU/mL.min-2 per mg/dL, P < .05) and glucose disposition index ([SI x phi 2] E 33.8 +/- 10 v 73.9 +/- 11 mg-1.dL.min-3 x 10(4), P < .02). Insulin sensitivity (SI) and glucose-mediated glucose disposal (SG) were unchanged (SI E 6.9 +/- 1.0 v 6.0 +/- 0.6 min-1 per microU/mL x 10(4); SG E 1.8 +/- 0.6 v 1.4 +/- 0.3 min-1 x 10(2)). Reduced glucose tolerance after prolonged extreme physical exercise was accompanied by reduced phi 2 and not by alterations of SI or SG, despite the marked increase of FFA levels. Elevated norepinephrine levels, reflecting activation of the sympathetic noradrenergic system, was also associated with the reduction in Kg. The reduction in phi 2 would promote mobilization of FFA, the predominant metabolic substrate in these endurance events.