Influence of nervous blockade on insulin-mediated glucose uptake in the human forearm

This study was undertaken to investigate if a nonpharmacologic increase in forearm blood flow (FBF) could increase forearm glucose uptake (FGU) during hyperinsulinemia. In 10 young volunteers, FBF and the arterial-venous glucose difference were measured in both arms during a 2-hour euglycemic hyperinsulinemic clamp procedure when 1 of the arms was subjected to axillary plexus nervous blockade with local anesthesia. FBF was measured in both arms by venous occlusion plethysmography. Nervous blockade, increasing FBF by more than 3-fold, did not improve insulin-mediated FGU. On the contrary, a tendency towards a reduced FGU compared with the control arm was seen (P =.07). Furthermore, while insulin increased FBF to a similar degree in both arms (+ 3.0 and 4.4 mL/min/100 mL tissue, P <.01 for both arms), nervous blockade abolished the rapid increase in glucose extraction seen in the control arm when insulin infusion was initiated. The present study showed that an increase in FBF induced by nervous blockade did not increase insulin-mediated FGU. On the contrary, a tendency towards a reduction was seen. Furthermore, insulin induced vasodilation in the blocked arm, but delayed the ability of insulin to promote glucose extraction, suggesting that the well-documented increase in skeletal muscle sympathetic nerve activity seen during acute hyperinsulinemia has metabolic rather than hemodynamic consequences.     

Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver

Aims/hypothesis We investigated the effect of elevated circulating NEFA on insulin-mediated hepatic glucose uptake (HGU) and whole-body glucose disposal (M) in eight healthy male subjects.Methods Studies were performed using positron emission tomography (PET) and [¹⁸F]-2-fluoro-2-deoxyglucose ([¹⁸F]FDG) during euglycaemic hyperinsulinaemia (0–120 min) and an Intralipid/heparin infusion (IL/Hep; –90–120 min). On a different day, similar measurements were taken during euglycaemic hyperinsulinaemia and saline infusion (SAL). Graphical and compartmental analyses were used to model liver data.Results Circulating NEFA increased approximately three-fold during IL/Hep, and declined by 81±7% in the SAL study (p0.01). Both M (–28±7%) and HGU (–25±9%) were significantly lowered by NEFA elevation (p=0.004 and p=0.035 respectively). In the whole data set, the decreases in M and HGU were positively correlated (r=0.78, p=0.038). No evidence of [¹⁸F]FDG outflow was detected during the scanning time. HGU was correlated with the phosphorylation rate parameter (r=0.71, p=0.003) as derived by compartmental modelling.Conclusions/interpretation In healthy men, NEFA impair insulin-mediated HGU and whole-body glucose uptake to a similar extent. Our data suggest that multiple intracellular NEFA targets may concur to down-regulate glucose uptake by the liver.Abbreviations FDG 2-fluoro-2-deoxyglucose - HGU hepatic glucose uptake - HKi influx rate constant - M whole-body glucose uptake - PET positron emission tomography - ROI region of interest - SGU splanchnic glucose uptake - SS sum of squares     

Effect of free fatty acids on glucose uptake and nonoxidative glycolysis across human forearm tissues in the basal state and during insulin stimulation

We tested whether FFAs influence glucose uptake by human peripheral tissues in vivo. Whole body glucose uptake, FFA turnover, energy expenditure and substrate oxidation rates, forearm glucose and FFA uptake, and nonoxidative glycolysis (net release of alanine and lactate) were measured in 14 normal male subjects in the basal state (0-240 min; serum insulin, approximately 5 microU/mL) and during euglycemic hyperinsulinemia (240-360 min; approximately 75 microU/mL) on 2 separate occasions, once during elevation of plasma FFA by infusions of Intralipid and heparin (plasma FFA, 4.6 +/- 0.1 vs. 4.2 +/- 0.4 mmol/L; 180-240 vs. 300-360 min) and once during infusion of saline (plasma FFA, 0.50 +/- 0.07 vs. 0.02 +/- 0.07 mmol/L, respectively). In the basal state, whole body glucose disposal remained unchanged, but the fate of glucose was significantly altered toward diminished oxidation (7.3 +/- 0.8 vs. 5.6 +/- 0.5 mumol/kg.min; P less than 0.05, saline vs. Intralipid) and increased nonoxidative glycolysis (P less than 0.05). Elevation of plasma FFA significantly increased forearm glucose uptake (1.0 +/- 0.6 vs. 2.4 +/- 0.7 mumol/kg.min; P less than 0.01) and nonoxidative glycolysis (net release of alanine and lactate, 0.4 +/- 0.5 vs. 1.2 +/- 0.4 mumol glucose equivalents/kg.min; P less than 0.05). During hyperinsulinemia, FFA decreased whole body glucose disposal (38 +/- 2 vs. 30 +/- 3 mumol/kg.min; P less than 0.001) due to a decrease in glucose oxidation (13 +/- 1 vs. 7 +/- 1 mumol/kg.min; P less than 0.01, saline vs. Intralipid), and forearm glucose uptake (31 +/- 4 vs. 24 +/- 6 mumol/kg.min; P less than 0.01, saline vs. Intralipid). Under these conditions, 7 +/- 2% and 3 +/- 1% (P less than 0.05) of forearm glucose uptake could be accounted for by nonoxidative glycolysis in the Intralipid and saline studies, respectively. In summary, 1) elevation of plasma FFA concentrations suppresses the rate of carbohydrate oxidation to a rate that, both basally and during hyperinsulinemia, is similar to that reported for insulin-independent glucose oxidation in the brain; 2) basally, forearm glucose uptake is increased by FFA; and 3) during hyperinsulinemia, FFA inhibit glucose uptake by forearm tissues. We conclude that the interaction between glucose and FFA fuels in human forearm tissues is dependent upon the ambient insulin concentration; the increase in basal glucose uptake would be compatible with the increase need of glucose for FFA reesterification; the decrease in insulin-stimulated glucose uptake supports operation of the glucose-FFA cycle in human forearm tissues.     

Effect of hyperammonemia on insulin-mediated glucose uptake in rats

In order to explain the abnormalities in glucose tolerance and insulin secretion previously observed in hyperammonemic humans and rats, the effect of hyperammonemia on insulin sensitivity was investigated in rats. The study was performed in normal rats compared to rats with either an exogenous hyperammonemia induced by intravenous ammonium supply, or with a chronic and endogenous hyperammonemia produced by a progressive portal stricture. In these animals, the endogenous insulin secretion was pharmacologically inhibited with an epinephrine-propranolol mixture (as verified in control groups by comparison of peripheral and portal immunoreactive insulin measures) and a 1-hr glucose infusion (40 mg/min/kg) was added with high or low insulin doses. The difference between the glucose steady state so obtained and the basal blood glucose level (ΔG) represents a direct measure of the rate of glucose disappearance and an estimation of insulin sensitivity or resistance. The results indicate, with low as well as with high insulin doses, that ΔG is higher (p < 0.001) in rats with exogenous or endogenous hyperammonemia than in normals. Among the portal-strictured rats, a group previously treated with neomycin differed from the untreated group both by a lower blood ammonia level and by a lower ΔG (p < 0.05); a linear regression existed between ΔG and ammonemia (p < 0.01) in these two groups. Consequently, the abnormalities in glucose tolerance noted in rats with exogenous or endogenous hyperammonemia may be partly explained by an increased insulin resistance.     

Plasma free fatty acid and glucose concentrations in Houssay dogs

Summary Results of two types of metabolic studies are reported in depancreatized-hypophysectomized dogs maintained without hormonal replacement therapy. The response to a glucose load indicated the presence of severe diabetes, although the animals were not ketonuric and fasting plasma sugars fluctuated around 200 mg %. The response to a single growth hormone injection was that of an acute reduction of the concentration of plasma FFA. Since this occurred in the complete absence of the action of insulin, mechanisms other than insulin-dependent esterification were involved.

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Zusammenfassung Es werden die Resultate von 2 metabolischen Studientypen bei pankreatektomierten-hypophysektomierten Hunden die man ohne hormonale Substitutionstherapie liess, mitgeteilt. Die Antwort auf die Glukosebelastung zeigte die Anwesenheit eines schweren Diabetes, wen auch die Tiere keine Ketonurie aufwiesen und der Nuechternblutzucker ungefaehr bei 200 mg% lag. Die Antwort auf eine einzige Injektion von Wachstumshormon bestand in einer akuten Abnahme der Konzentration der plasmatischen FFA. Da dies bei kompletter Abwesenheit einer Insulinwirkung stattfand, waren Mechanismen im Spiel, die sich von der insulin-abhaengigen Veresterung unterschieden.

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Resumen Se dan a conocer los resultados de dos tipos de estudios metabólicos en perros despancreatizados e hipofisectomizados mantenidos sin tratamiento hormonal sustitutivo. La respuesta a la carga de glucosa indicó la presencia de una diabetes grave, si bien los animales no fuesen quetonúricos y la glicemia en ayunas oscilase en los 200 mg % aproximadamente. La respuesta a una sola inyección de hormona del crecimiento correspondía a la de una reducción aguda de la concentración de los FFA plasmáticos. El hecho de que esto se verificó en completa ausencia de acción insulínica, significa que estaban implicados mecanismos distintos a los de la esterificación insulino-dependiente.

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Resume L'A. rapporte les résultats de deux types d'études métaboliques effectuées chez des chiens privés du pancréas et de l'hypophyse sans aucun traitement hormonal substitutif. La réaction à la charge de glucose a indiqué, chez ces animaux, la présence d'un diabète grave, malgré l'absence de cétonurie et un taux glycémique atteignant environ 200 mg % à jeun. La réaction à une seule injection d'hormone de la croissance correspondait à celle d'une réduction aiguë de la concentration de FFA plasmatiques. Cette situation s'étant manifestée en l'absence complète d'action insulinique, il y a lieu de penser à d'autres mécanismes que l'estérification dépendant de l'insuline.

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Riassunto Vengono riferiti i risultati di due tipi di studi metabolici in cani spancreati-ipofisectomizzati mantenuti senza terapia ormonale sostitutiva. La risposta al carico di glucosio ha indicato la presenza di un diabete grave, sebbene gli animali non fossero chetonurici e la glicemia a digiuno oscillasse intorno ai 200 mg %. La risposta ad una sola iniezione di ormone dell'accrescimento consistette in una riduzione acuta della concentrazione degli FFA plasmatici. Dal momento che ciò si è verificato in completa assenza di azione insulinica, erano implicati meccanismi diversi dalla esterificazione insulino-dipendente.

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Supported by the Medical Research Council of Canada, grant MA 2288, and Hoechst Pharmaceuticals of Canada.Il lavoro è stato finanziato dal Medical Research Council del Canada, assegnazione MA 2288 e dalla Hoechst Pharmaceuticals of Canada.

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Recipient of a Denison Mines Postdoctoral Fellowship.Vincitore di una Borsa di Studio di Perfezionamento UniversitarioDenison Mines.     

In vivo regulation of non-insulin-mediated and insulin-mediated glucose uptake by epinephrine

In vivo glucose uptake (Rd) occurs via two mechanisms: 1) insulin-mediated glucose uptake (IMGU), which occurs in insulin-sensitive tissues, and 2) noninsulin-mediated glucose uptake (NIMGU), which occurs in both insulin-sensitive and insulin-insensitive tissues. Thus, in the postabsorptive (basal) state Rd = IMGU + NIMGU. To determine whether these two pathways for in vivo glucose disposal are regulated independently, we studied the effect of stress levels of epinephrine (EPI) on IMGU and NIMGU in seven normal men after an overnight fast. To study NIMGU, somatostatin (600 micrograms/hr) was infused to suppress endogenous insulin secretion, and glucose turnover was measured isotopically while the serum glucose level was clamped at about 200 mg/dL for 240 min. Separate studies were done during the infusion of saline or EPI (0.2 microgram/kg X min). The final 120 min of each study were used for data analysis. Under these conditions insulin action is absent and Rd = NIMGU. NIMGU was 210 +/- 15 (+/- SEM) and 200 +/- 17 mg/min during saline and EPI treatment, respectively (P = NS). Therefore, EPI has no ability to modulate NIMGU. To measure the effect of EPI on Rd, hyperglycemic (200 mg/dL) hyperinsulinemic clamp (30 mU/M2 X min) studies were performed during the infusion of saline and EPI. EPI decreased Rd by 46 +/- 6% (751 +/- 85 to 405 +/- 43 mg/min; P less than 0.01). When the effect of EPI on IMGU (Rd - NIMGU) was considered separately, the inhibitory effect of EPI was more potent, as indicated by a 61 +/- 12% decrease in IMGU. In conclusion, 1) EPI inhibits IMGU, but has no effect on NIMGU; 2) when NIMGU is taken into account, EPI has a more potent ability to inhibit IMGU than previously found; and 3) the systems responsible for NIMGU and IMGU are independently regulated.     

Lack of effect of alpha- and beta-adrenergic inhibition on forearm glucose uptake despite differences in forearm blood flow in healthy humans

Insulin has both sympathoexcitatory and vasodilatory actions. It is unclear how these interact to affect muscular glucose uptake. The current study was designed to determine the systemic and local contributions of alpha- and beta-adrenergic activity to muscle glucose uptake. Forearm blood flow (FBF, plethysmography), arterial-venous glucose difference (AV-diff), and forearm glucose uptake (FGU) were measured during a 40-mU/m(2)/min insulin infusion with 120 minutes of euglycemia in 6 normal subjects (age, 28.8 +/- 4.9 years, mean +/- SD). Each subject was studied 5 times, once each with intravenous propranolol (IV PROP, 80 microg/min), intravenous phentolamine (IV PHEN, 500 microg/min), intra-arterial propranolol (IA PROP, 25 microg/min), intra-arterial phentolamine (IA PHEN, 12 microg/min/100 mL forearm tissue), and saline (SAL). FBF did not change during insulin with SAL, IA PROP, or IV PROP, but increased during insulin with IA PHEN and IV PHEN (P <.05). Despite the increased glucose delivery during insulin plus IA PHEN and IV PHEN, FGU did not differ between study sessions at any time during the insulin infusion. This was due to the lower AV-diff during insulin with IA PHEN and IV PHEN compared to the other studies (P <.05). AV-diff negatively correlated with FBF at the end of the insulin infusion (P <.001) for all studies. In normal humans, inhibition of basal sympathetic activity does not alter muscular glucose uptake. The increased insulin-induced vasodilation during alpha-adrenergic inhibition suggests that insulin-induced sympathetic activation prevents excess vasodilation. This inhibition does not alter glucose uptake because changes in flow are counterbalanced by changes in glucose extraction.     

Exogenous insulin replacement in type 2 diabetes reverses excessive hepatic glucose release,but not excessive renal glucose release and impaired free fatty acid clearance

In type 2 diabetes renal and hepatic glucose release are increased and free fatty acids (FFA) clearance is reduced. Restoration of normoglycemia by exogenous insulin replacement normalizes overall glucose release and plasma FFA concentrations. However, it is unclear to what extent normalization of overall glucose release is due to suppression of hepatic (HGR) and renal glucose release (RGR) and whether the abnormal FFA clearance is improved. We therefore determined overall, renal, and hepatic glucose release, as well as systemic FFA release and clearance by tracer techniques in type 2 diabetic subjects with (DM(+)) and without (DM(-)) physiologic overnight insulin infusion and in nondiabetic volunteers (NV). Insulin infusion normalized plasma glucose (5.3 +/- 0.1 v 5.2 +/- 0.1 mmol/L in NV) and overall glucose release (10.1 +/- 0.7 v 10.6 +/- 0.4 micromol x kg(-1) x min(-1) in NV), (both P >.9). Values in DM(-) were 9.1 +/- 0.6 mmol/L and 14.6 +/- 0.8 micromol x kg(-1) x min(-1), respectively (both P <.001 v DM(+) and NV). The correction of overall glucose release in DM(+) was due to suppression of HGR to rates below normal (6.11 +/- 0.53 v 8.67 +/- 0.44 micromol x kg(-1) x min(-1) in NV, P <.03). RGR remained increased (3.91 +/- 0.38 v 1.90 +/- 0.28 micromol x kg(-1) x min(-1) in NV, P <.002) and was similar to DM(-) (3.97 +/- 0.33 micromol x kg(-1) x min(-1), P >.9). Insulin infusion also normalized plasma FFA levels (450 +/- 45 v 476 +/- 42 in NV, P >.9 and v613 +/- 33 micromol/L in DM(-), P <.04). This was due to suppression of FFA release to below normal (4.04 +/- 0.45 v 5.25 +/- 0.25 micromol x kg(-1) x min(-1) in NV, P <.04). Plasma FFA clearance remained reduced (7.2 +/- 1.0 v 11.4 +/- 1.2 mL x kg(-1) x min(-1) in NV, P <.04) and was similar to DM(-) (7.3 +/- 0.5 mL x kg(-1) x min(-1), P >.9). We conclude that in contrast to the excessive HGR, excessive RGR and impaired FFA clearance are not corrected by acute exogenous insulin replacement.     

Differences in free fatty acid and glucose metabolism of human blood neutrophils and lymphocytes.

Comparison of isolated human neutrophils and lymphocytes in short-term tissue culture revealed marked differences in their rates of lipid biosynthesis. Ficoll-Hypaque gradients were used to separate lymphocytes and neutrophils from the blood of normal subjects. Neutrophils incorporated more palmitate into cell lipids (151.0 +/- 16.6 nmole/hr/10(8) cells) than lymphocytes (41.6 +/- 4.1). By contrast, the lymphocytes oxidized more palmitate (8.3 +/- 0.5 nmole/hr/10(8) cells) as compared to neutrophils (1.1 +/- 0.1). The greater fatty acid uptake by the neutrophils was due to a sixfold greater rate of incoporation of palmitate into their triglyceride fraction. Triglyceride synthesis by neutrophils increased as the molar ratio of free fatty acid to albumin was raised, whereas incorporation into phospholipids remained relatively constant; there was preferential labeling of neutrophil triglycerides throughout the physiologic range. Studies using linoleate and oleate gave similar results. The distribution of radioactivity into various phospholipids determined by thin-layer chromatography was similar for the two cell types. When labeled glucose was used as a substrate to measure incorporation primarily into the glycerol backbone of the cell lipids, neutrophils incorporated more radioactivity into total lipids and triglycerides than lymphocytes. These results indicate that neutrophils take up much more fatty acid than lymphocytes primarily because they synthesize much larger quantities of triglycerides, a storage form. Since cellular triglycerides may act as a source of fatty acid for lecithin synthesis during phagocytosis, the greater rate of fatty acid incorporation in the neutrophil may reflect a metabolic pattern that permits efficient phagocytosis.     

Comparison of free fatty acid and glyceride--fatty acid uptake by human adipose tissue

A comparison has been made of the uptake of palmitate and triglyceride into human adipose tissue. Both substrates are converted into tissue lipid at similar rates over an incubation period of 2 hr; the uptake of triglyceride is proportional to the amount of tissue in the incubation medium. The assimilation of triglyceride by human adipose tissue requires preincubation of the triglyceride emulsion with serum; depends on the presence of glucose in the incubation medium; and radioactivity from glyceryl-tripalmitin-T is incorporated in preference to ¹⁴C-glyceryl-tripalmitin. Fasting reduced both the uptake of triglyceride into tissue lipid and the esterification of palmitate by the tissue. Fluoride (20 mM) significantly inhibits the esterification of palmitate by human adipose tissue without altering the incorporation of triglyceride. At higher concentrations of fluoride (80 mM) there is some inhibition of triglyceride uptake.     

Acute elevation of free fatty acids impairs hepatic glucose uptake in conscious rats

To investigate the dose-dependent effect of free fatty acid (FFA) on the hepatic glucose uptake (HGU), we determined hepatic glucose fluxes by a dual tracer technique during the basal state and euglycemic hyperinsulinemic clamp combined with a portal glucose load in three groups of rats given saline (saline), low-dose lipid (lipid-L), or high-dose lipid infusion (lipid-H). In the basal state, lipid infusion dose-dependently increased plasma FFA (saline, 400 +/- 50; lipid-L, 550 +/- 30; lipid-H, 1700 +/- 270 micromol l(-1); mean +/- S.E). Endogenous glucose production (EGP) in lipid-H was 63.5 +/- 5.5 micromol kg(-1) min(-1) and significantly higher than in the saline and lipid-L (40.2 +/- 2.9, 47.6 +/- 3.1 micromol kg(-1) min(-1), respectively). During euglycemic hyperinsulinemic clamp, plasma FFA decreased to 130 +/- 30 micromol l(-1) in saline, but remained at basal levels in lipid-L and lipid-H (470 +/- 30 and 1110 +/- 180 micromol l(-1), respectively). Insulin-suppressed EGP was complete in saline and lipid-L, but impaired in lipid-H (38.0 +/- 6.4 micromol kg(-1) min(-1)). Elevated FFA dose-dependently reduced HGU (saline, 12.2 +/- 0.9; lipid-L, 8.6 +/- 0.6; lipid-H, 4.7 +/- 1.4 micromol kg(-1) min(-1)). In conclusion, acutely elevated FFA impairs HGU as well as insulin-mediated suppression of EGP during hyperinsulinemic clamp with portal glucose loading. Impaired hepatic glucose uptake associated with elevated FFA may contribute to the development of insulin resistance in obesity and type 2 diabetes.     

Regulation of glucose metabolism by free fatty acid availability in septic and nonseptic rats.

An inhibitory effect of fatty acid oxidation on glucose uptake and oxidation has been demonstrated in heart and skeletal muscle under certain experimental conditions. This reciprocal relationship has been termed the glucose-fatty acid cycle. The purpose of the present study was to determine under in vivo conditions whether this interaction was operational in various nonmuscle tissues, and whether infection altered the activity of this cycle. Oral administration of alpha-methylpalmoxirate (MPA; 75 mg/kg), a known inhibitor of long-chain fatty acid oxidation, suppressed hepatic glucose production by 54% and increased whole body glucose disappearance by 15% in nonseptic rats. In contrast, MPA produced a larger reduction of glucose output in septic rats, but did not enhance glucose disposal. In vivo glucose uptake (Rg) by individual tissues was determined using the tracer 2-deoxyglucose technique. In nonseptic animals, MPA increased Rg in "working" muscles (heart and diaphragm; 12-fold and two-fold respectively), but not in "resting" skeletal muscles. MPA increased the Rg of heart and diaphragm to the same level in septic animals. Inhibition of fatty acid oxidation in nonseptic rats also enhanced Rg in liver (174%), spleen (158%), lung (153%), ileum (52%), skin (28%), kidney (115%), and epididymal fat (135%). In septic rats, MPA only increased Rg in the ileum (23%) and kidney (50%). This increased glucose uptake was independent of increases in plasma glucose and insulin concentrations. The infusion of heparin and intralipid, which increased circulating levels of fatty acids, failed to produce consistent changes in either the whole body glucose turnover or glucose uptake by individual tissues. We conclude that under basal in vivo conditions the inhibition of fatty acid oxidation suppresses glucose production and increases peripheral glucose disposal in nonseptic animals. These data support the presence of the glucose-fatty acid cycle in nonmuscle tissues and emphasizes its importance in whole body glucose homeostasis in situations where fatty acid oxidation is impaired. Infection increases glucose uptake by nonmuscle tissues which, for the most part, cannot be further enhanced by the inhibition of lipid oxidation.     

Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus

The ability of insulin to stimulate tissue glucose uptake and lower plasma FFA concentrations was quantified in 12 individuals with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM), further subdivided into obese and nonobese subjects. Measurements were made during 5-h glucose clamp studies, carried out at plasma insulin concentrations of about 10 microU/ml (0-150 min) and about 60 microU/ml (150-300 min). Differences between the patient groups were compared by two-way analysis of variance. The ability of insulin to either suppress plasma FFA concentrations or stimulate glucose uptake was significantly reduced (P less than 0.001) in patients with NIDDM, and this was true of both the obese and nonobese groups. The defect in the ability of insulin to suppress plasma FFA concentrations in patients with NIDDM was more apparent at the lower insulin concentration, whereas resistance to insulin-stimulated glucose uptake in NIDDM was more dramatic at the high insulin concentration. Finally, a significant correlation (r = -0.67; P less than 0.001) between insulin-stimulated glucose uptake and plasma FFA concentration was found in the entire group. These data emphasize the fact that patients with NIDDM are resistant to multiple actions of insulin, and that the magnitudes of the defect in insulin suppression of plasma FFA levels and stimulation of tissue glucose uptake are roughly comparable.     

Reduced insulin-mediated glucose uptake by euglycemic clamp in offspring of patients with type 2 diabetes.

Family studies point to an important genetic element in the genesis of type 2 diabetes. A variety of metabolic abnormalities have been documented in offspring of patients with type 2 diabetes. It has not been shown, however, at what age reduced insulin sensitivity is demonstrable using the sensitive the euglycemic clamp technique. To address this issue we screened 425 consecutive type 2 diabetic patients and examined all available (n = 48) normotensive, normoglycemic, non-smoking offspring (mean age 31.4+/-0.9 years) and compared them to 22 healthy offspring of non-diabetic parents (controls). The two groups were of similar age and BMI. Measurements in offspring and controls included baseline IRI, tissue glucose uptake (TGU, using euglycemic hyperinsulinemic clamp technique), and 24 hour ambulatory blood pressure (ABP). TGU was significantly (p < 0.001) lower in offspring of diabetic parents (338.8+/-19.9 (mol/kg/min) when compared to controls (516.6+/-22.2 micromol/kg/min). 24 h systolic ABP was significantly higher (p < 0.02) in propositi compared to controls (121.2+/-2.2 mm Hg and 113.8+/-1.7 mm Hg, respectively). No difference in triglycerides concentration was found. A borderline negative correlation was observed, however, between triglyceride levels and TGU (R = -0.48, p < 0.001). TGU was not related to the presence or absence of diabetic nephropathy in the parents. We conclude: Insulin resistance and various facets of the metabolic syndrome are demonstrable even at age 30 years in young non-obese, normotensive offspring of patients with type 2 diabetes. These disturbances are not related to the presence of microvascular complications in parents.