Insulin action in adipose tissue and muscle in hypothyroidism

BACKGROUND: Although insulin resistance in thyroid hormone excess is well documented, information on insulin action in hypothyroidism is limited. METHODS: To investigate this, a meal was given to 11 hypothyroid (HO; aged 45 +/- 3 yr) and 10 euthyroid subjects (EU; aged 42 +/- 4 yr). Blood was withdrawn for 360 min from veins (V) draining the anterior abdominal sc adipose tissue and the forearm and from the radial artery (A). Blood flow (BF) in adipose tissue was measured with 133Xe and in forearm with strain-gauge plethysmography. Tissue glucose uptake was calculated as (A-V)glucose(BF), lipoprotein lipase as (A-V)Triglycerides(BF), and lipolysis as [(V-A)glycerol(BF)]-lipoprotein lipase. RESULTS: The HO group had higher glucose and insulin levels than the EU group (P < 0.05). In HO vs. EU after meal ingestion (area under curve 0-360 min): 1) BF (1290 +/- 79 vs. 1579 +/- 106 ml per 100 ml tissue in forearm and 706 +/- 105 vs. 1340 +/- 144 ml per 100 ml tissue in adipose tissue) and glucose uptake (464 +/- 74 vs. 850 +/- 155 micromol per 100 ml tissue in forearm and 208 +/- 42 vs. 406 +/- 47 micromol per 100 ml tissue in adipose tissue) were decreased (P < 0.05), but fractional glucose uptake was similar (28 +/- 6 vs. 33 +/- 6% per minute in forearm and 17 +/- 4 vs. 14 +/- 3% per minute in adipose tissue); 2) suppression of lipolysis by insulin was similar; and 3) plasma triglycerides were elevated (489 +/- 91 vs. 264 +/- 36 nmol/liter.min, P < 0.05), whereas adipose tissue lipoprotein lipase (42 +/- 11 vs. 80 +/- 21 micromol per 100 ml tissue) and triglyceride clearance (45 +/- 10 vs. 109 +/- 21 ml per 100 ml tissue) were decreased in HO (P < 0.05). CONCLUSIONS: In hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) suppression of lipolysis by insulin is not impaired; and 3) hypertriglyceridemia is due to decreased clearance by the adipose tissue.     

Insulin-stimulated rates of glucose uptake in muscle in hyperthyroidism: the importance of blood flow

BACKGROUND: In hyperthyroidism, although hepatic insulin resistance is well established, information on the effects of insulin on glucose uptake in skeletal muscle is variable. METHODS: To investigate this, a meal was given to nine hyperthyroid (HR) and seven euthyroid (EU) subjects. Blood was withdrawn for 360 min from a forearm deep vein and the radial artery for measurements of insulin and glucose. Forearm blood flow (BF) was measured with strain-gauge plethysmography. Glucose flux was calculated as arteriovenous difference multiplied by BF and fractional glucose extraction as arteriovenous difference divided by arterial glucose concentrations. RESULTS: Both groups displayed comparable postprandial glucose levels, with the HR having higher insulin levels than the EU. In the forearm of HR vs. EU: 1) glucose flux was similar [area under the curve (AUC)(0-360) 673 +/- 143 vs. 826 +/- 157 micromol per 100 ml tissue]; 2) BF was increased (AUC(0-360) 3076 +/- 338 vs. 1745 +/- 145 ml per 100 ml tissue, P = 0.005); and 3) fractional glucose extraction was decreased (AUC(0-360) 14.5 +/- 3 vs. 32 +/- 5%min, P = 0.03). CONCLUSIONS: These results suggest that, in hyperthyroidism, insulin-stimulated glucose uptake in muscle is impaired; this defect is corrected, at least in part, by the increases in BF.     

Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal.

Physiological actions of insulin include suppression of fat mobilization from adipose tissue and activation of adipose tissue lipoprotein lipase. Here, we report measurements of adipose tissue hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action in vivo in 10 normal and eight obese subjects, with the latter group having varying degrees of glucose intolerance. HSL and LPL actions (per gram of adipose tissue) were similar in the two groups, after an overnight fast. In the normal subjects, HSL action was suppressed after a meal (by 75% +/- 6% between 60 to 300 minutes, P less than .01), and the action of LPL was increased (clearance of circulating triacylglycerol [TAG] increased by 140% +/- 57% at 300 minutes, P less than .05). Despite hyperinsulinemia, these responses were blunted in the obese subjects (P less than .05 for each change being less than in normal group). The adipose tissue of the obese subjects showed continued nonesterified fatty acid (NEFA) release at a time when NEFA mobilization was completely suppressed in the normal group. Both impaired suppression of HSL and low fractional retention of fatty acids for reesterification within the adipose tissue contributed to this abnormal NEFA release. Impaired activation of LPL was associated with a greater absolute increase in plasma TAG concentration postprandially in the obese. In obese subjects, adipose tissue HSL and LPL fail to respond to immunoreactive insulin postprandially, which may be an important maladaptation in terms of lipoprotein metabolism and risk of coronary heart disease.     

Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis

OBJECTIVES: Insulin resistance is nearly universal in patients with nonalcoholic steatohepatitis (NASH) when tested by glucose tolerance tests or clamp methods. However, the pattern of insulin resistance in these patients after a physiological challenge is unknown. We conducted a study to characterize the metabolic response to a mixed meal in nondiabetic patients with NASH (NDN) and to identify anthropometric determinants of insulin resistance in these patients. METHODS: Serum insulin, C-peptide, glucose, and free fatty acid (FFA) levels were measured at 0, 30, 60, 90, and 120 min after a 500-kcal standard meal in 18 NDN and 18 age-, gender-, and body mass index (BMI)-matched controls. Correlations were made between insulin resistance and various anthropometric, calorimetric, and serological variables. RESULTS: Compared with controls, NDN had significantly higher levels of insulin and C-peptide at baseline and after the mixed meal. However, glucose levels were not different either at baseline or after the meal. NDN had higher fasting levels of FFA than the controls (459 +/- 190 vs 339 +/- 144 micro mol/L, respectively, p = 0.03); however, meal-induced suppression in lipolysis was similar between the two groups (39 +/- 113% vs 46 +/- 60%, p = 0.8). Insulin resistance was significantly correlated with BMI (r = 0.39, p = 0.02) and visceral fat (r = 0.50, p = 0.004). Whereas BMI, percent total body fat, and subcutaneous abdominal fat were similar between the groups, the NASH group had significantly higher percent visceral fat compared with controls (28 +/- 10% vs 22 +/- 14%, p = 0.02). CONCLUSIONS: NDN are significantly hyperinsulinemic, both at fasting and after the mixed meal; however, their glucose homeostasis and suppression in lipolysis after a meal challenge are maintained. Insulin resistance in these patients is likely related to their higher visceral fat mass.     

Postprandial regulation of blood lipids and adipose tissue lipoprotein lipase in type 2 diabetes patients and healthy control subjects

BACKGROUND/AIM: In type 2 diabetes and other insulin-resistant conditions, postprandial hypertriglyceridaemia is an important metabolic perturbation. To further elucidate alterations in the clearance of triglyceride-rich lipoproteins in type 2 diabetes we focused on the nutritional regulation of adipose tissue lipoprotein lipase (LPL). SUBJECTS AND METHODS: Eight subjects with type 2 diabetes and eight age-, sex- and body mass index (BMI)-matched control subjects underwent subcutaneous abdominal adipose tissue biopsies in the fasting state and 3.5 h following a standardized lipid-enriched meal. LPL activity and mass were measured in adipose tissue and also in plasma after an intravenous injection of heparin. RESULTS: Postprandial, but not fasting, triglycerides were significantly higher in the diabetic subjects than in the control subjects (3.0+/-0.4 vs 2.0+/-0.2 mmol/l, P=0.028). Adipose tissue LPL activity was increased following the meal test by approximately 35-55% (P=0.021 and 0.004, respectively). There was no significant difference between the groups in this respect. The specific enzyme activity of LPL was not altered in the postprandial state. Fasting and postprandial adipose tissue LPL activity as well as post-heparin plasma LPL activity tended to be lower among the diabetes patients (NS). There was a significant and independent inverse association between insulin resistance (homeostasis model assessment insulin resistance (HOMA-IR) index) vs post-heparin plasma LPL activity and postprandial triglyceride levels, respectively. Adipose tissue LPL activity was related to insulin action in vitro on adipocyte glucose transport, but not to HOMA-IR. CONCLUSION: Following food intake adipose tissue LPL activity is enhanced to a similar degree in patients with type 2 diabetes and in healthy control subjects matched for BMI, age and gender. If LPL dysregulation is involved in the postprandial hypertriglyceridaemia found in type 2 diabetes, it should occur in tissues other than subcutaneous fat.     

Lack of effect of a physiological elevation of plasma non-esterified fatty acid levels on insulin secretion

Elevated plasma non-esterified fatty acid (NEFA) levels in obese subjects may contribute to their higher insulin secretory rates by direct effects on the islet B-cells. This may involve short-term metabolic effects, or long-term effects on islet B-cell mass, which is characteristically increased in obesity. We examined the effects of elevating plasma NEFA levels for 5.5 to 7 h on insulin secretion after an overnight fast and during a 90 min 12 mmol/l hyperglycemic clamp in 9 normal women (40.1 +/- 9.5 years [mean +/- SD]; BMI: 25.2 +/- 3.72 kg/m(2) ). Subjects were studied twice. In one study plasma NEFA levels were increased approximately 2-fold by infusion of 20% Intralipid (60 ml/h) and heparin (900 U/h) for 5.5 h before and throughout the glucose clamp. Elevated NEFA levels were associated with a small increase in fasting plasma glucose (5.0 +/- 0.1 vs 4.7 +/- 0.1 mmol/l, P <0.05) and C-peptide levels (0.54 +/- 0.09 vs 0.41 +/- 0.06 nmol/l, P <0.05). The increase in fasting insulin levels did not, however, reach statistical significance (9.0 +/- 2.5 vs 5.3 +/- 1.4 mU/l, NS). During the glucose clamp, plasma NEFA levels were suppressed to very low levels in the saline control study. Although plasma NEFA levels also fell in the lipid/heparin study, they remained significantly higher than on the control day, and somewhat higher than might be expected postprandially in obese subjects. During the glucose clamps, plasma glucose, insulin, and C-peptide profiles were similar on the two study days. No difference in either first or second phase insulin secretion was observed between the two studies. In conclusion, our findings do not support the idea that the exaggerated insulin secretion in obesity is mediated by short-term effects of plasma NEFA levels on islet B-cell metabolism, independent of plasma glucose levels.     

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

OBJECTIVE: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. METHODS: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88+/-0.13 mg) (B); GH+acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose and indirect calorimetry. RESULTS: GH increased basal free fatty acid (FFA) levels by 74% (P=0.0051) and insulin levels by 93% (P=0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61+/-8.03 vs 12.74+/-5.50 micromol/kg per min (s.d.), P=0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r=-0.638, P<0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35+/-5.65 vs 12.74+/-5.50 micromol/kg per min, P=0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32+/-3.00 vs 5.88+/-2.39 micromol/kg per min, P=0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r=-0.867, P=0.0093) and during insulin-stimulated (r=-0.927, P=0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86+/-5.22 vs 8.67+/-6.65 micromol/kg per min, P=NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99+/-1.98 vs 11.73+/-2.38 micromol/kg per min, P=NS for B vs A and 11.55+/-2.7 vs 10.99+/-1.98 micromol/kg per min, P=NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14+/-8.74 vs 16.61+/-8.03 micromol/kg per min, P=0.0077 for D vs A) and this was again due to enhanced fasting (7.90+/-2.68 vs 5.16+/-2.28 micromol/kg per min, P=0.01 for D vs A) and insulin-stimulated (9.78+/-3.68 vs 7.95+/-2.64 micromol/kg per min, P=0.07 for D vs A) glucose oxidation. CONCLUSION: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.     

Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy.

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.     

Oral spray insulin in treatment of type 2 diabetes: a comparison of efficacy of the oral spray insulin (Oralin) with subcutaneous (SC) insulin injection, a proof of concept study

OBJECTIVE: Proof-of-concept study of evaluation of metabolic effect of novel oral spray insulin (Oralin) formulation at breakfast time in subjects with type 2 diabetes on multiple daily injections. RESEARCH DESIGN AND METHODS: This was an open-label, crossover, randomized study in (n = 23) subjects with type 2 diabetes on multiple daily injections. Subjects received each treatment, in random order, 3 to 7 days apart-a daily dose of SC injection (0.1 u/kg) on one occasion and Oralin spray (100 u) at time 0 min on another occasion. Subjects were given a standard breakfast containing 360 cal (Sustacal liquid meal) 10 min after the dose. Blood samples were taken at regular intervals to measure glucose, insulin, and C-peptide. RESULTS: The 30- and 60-min postprandial glucose levels were significantly lowered with Oralin versus that with the injection treatment (146 +/- 5 mg/dL Oralin vs 184 +/- 7 mg/dL injection at 30 min and 192 +/- 6 mg/dL Oralin vs 236 +/- 9 mg/dL injection, p < 0.003 at 60 min). The rise in serum insulin levels was significantly higher (Cmax = 98 +/- 6 uU/mL for Oralin at 30 min vs 65 +/- 3 uU/ml injection, p < 0.001). The reduction in C-peptide was greater in Oralin during the first 60 min (1.38 +/- 0.21 ng/mL Oralin vs 1.75 +/- 0.38 ng/mL injection, p < 0.001). CONCLUSIONS: This proof-of-concept study results demonstrated that Oralin could be used as meal insulin in place of mealtime-insulin injections in subjects with type 2 diabetes to regulate the postprandial glucose levels.     

NO-1886 (ibrolipim), a lipoprotein lipase activator, increases the expression of uncoupling protein 3 in skeletal muscle and suppresses fat accumulation in high-fat diet-induced obesity in rats

Although the lipoprotein lipase (LPL) activator NO-1886 shows antiobesity effects in high-fat-induced obese animals, the mechanism remains unclear. To clarify the mechanism, we studied the effects of NO-1886 on the expression of uncoupling protein (UCP) 1, UCP2, and UCP3 in rats. NO-1886 was mixed with a high-fat chow to supply a dose of 100 mg/kg to 8-month-old male Sprague-Dawley rats. The animals were fed the high-fat chow for 8 weeks. At the end of the administration period, brown adipose tissue (BAT), mesenteric fat, and soleus muscle were collected and levels of UCP1, UCP2, and UCP3 messenger RNA (mRNA) were determined. NO-1886 suppressed the body weight increase seen in the high-fat control group after the 8-week administration (585 +/- 39 vs 657 +/- 66 g, P < .05). NO-1886 also suppressed fat accumulation in visceral (46.9 +/- 10.4 vs 73.7 +/- 14.5 g, P < .01) and subcutaneous (43.1 +/- 18.1 vs 68.9 +/- 18.8 g, P < .05) tissues and increased the levels of plasma total cholesterol and high-density lipoprotein cholesterol in comparison to the high-fat control group. In contrast, NO-1886 decreased the levels of plasma triglycerides, nonesterified free fatty acid, glucose, and insulin. NO-1886 increased LPL activity in soleus muscle (0.082 +/- 0.013 vs 0.061 +/- 0.016 mumol of free fatty acid per minute per gram of tissue, P < .05). NO-1886 increased the expression of UCP3 mRNA in soleus muscle 3.14-fold (P < .01) compared with the high-fat control group without affecting the levels of UCP3 in mesenteric adipose tissue and BAT. In addition, NO-1886 did not affect the expression of UCP1 and UCP2 in BAT, mesenteric adipose tissue, and soleus muscle. In conclusion, NO-1886 increased the expression of UCP3 mRNA and LPL activity only in skeletal muscle. Therefore, a possible mechanism for NO-1886's antiobesity effects in rats may be the enhancement of LPL activity in skeletal muscle and the accompanying increase in UCP3 expression.     

Effect of liraglutide on estimates of lipolysis and lipid oxidation in obese patients with stable coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial

Elevated levels of non-esterified fatty acids (NEFA) play a role in insulin resistance, impaired beta-cell function and they are a denominator of the abnormal atherogenic lipid profile that characterizes obese patients with type 2 diabetes (T2DM). We hypothesized that the GLP-1 receptor agonist liraglutide, in combination with metformin, would reduce lipolysis. In a randomized, double-blind, placebo-controlled, cross-over trial, 41 T2DM patients with coronary artery disease were randomized and treated with liraglutide-metformin vs placebo-metformin during 12- + 12-week periods with a wash-out period of at least 2 weeks before and between the intervention periods. NEFA kinetics were estimated using the Boston Minimal Model of NEFA metabolism, with plasma NEFA and glucose levels measured during a standard 180-minute frequently sampled intravenous glucose tolerance test. Liraglutide-metformin reduced estimates of lipolysis. Furthermore, placebo-metformin increased estimates of lipid oxidation, while treatment with liraglutide eliminated this effect. We conclude that liraglutide exerts a clinically relevant reduction in estimates of lipolysis and lipid oxidation which is explained, in part, by improved insulin secretion, as revealed by an intravenous glucose tolerance test.     

Regulation of non-esterified fatty acid and glycerol concentration by insulin in normal individuals and patients with type 2 diabetes.

Plasma glycerol and non-esterified fatty acid (NEFA) concentrations were determined in the basal state and in response to physiological hyperinsulinaemia in 30 non-obese individuals, 15 with Type 2 diabetes and 15 with normal glucose tolerance. Patients with Type 2 diabetes had higher basal concentrations of both glycerol (81 +/- 7 (+/- SE) vs 61 +/- 7 mumol l-1, p less than 0.05) and NEFA (842 +/- 40 vs 630 +/- 46 mumol l-1, p less than 0.002). Plasma NEFA and glycerol concentrations fell in both groups when steady-state plasma insulin concentrations were raised to approximately 450 pmol l-1 by an infusion of exogenous insulin, but plasma concentrations of glycerol (28 +/- 3 vs 13 +/- 3 mumol l-1, p less than 0.002) and NEFA (186 +/- 15 vs 109 +/- 14 mumol l-1, p less than 0.001) were still higher in patients with Type 2 diabetes. Percentage decrease in glycerol from basal levels in response to insulin was significantly less in patients with Type 2 diabetes than in control subjects (64 +/- 3 vs 80 +/- 3%, p less than 0.005); percentage decrease in plasma NEFA concentration was similar in the two groups (78 +/- 3 vs 80 +/- 4%). These results suggest that both plasma glycerol and NEFA concentrations are higher than normal in patients with Type 2 diabetes when measured at the same insulin concentration, both under basal conditions and in response to physiological hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin regulation of plasma free fatty acid concentrations is abnormal in healthy subjects with muscle insulin resistance

This study evaluated the ability of insulin to regulate free fatty acid (FFA) concentrations in healthy nondiabetic subjects selected to be either insulin-resistant or -sensitive on the basis of insulin-mediated glucose disposal by muscle. Comparisons of steady-state plasma glucose (SSPG), insulin (SSPI), and FFA concentrations were made at the end of 3 infusion periods: (1) under basal insulin conditions (approximately 10 microU/mL), (2) in response to isoproterenol-induced stimulation of lipolysis at the same basal insulin concentration, and (3) following inhibition of isoproterenol-induced lipolysis by a 2-fold increase in the insulin concentration. The results showed that steady-state FFA concentrations were significantly higher under basal conditions (360 +/- 73 v 158 +/- 36 microEq/L, P = .02), in response to isoproterenol-induced lipolysis (809 +/- 92 v433 +/- 65 microEq/L, P = .005), and following insulin inhibition of isoproterenol-induced lipolysis (309 +/- 65 v 159 +/- 37 microEq/L, P = .06). These differences were found despite the fact that SSPG concentrations were also higher in insulin-resistant individuals during all 3 infusion periods. These results demonstrate that the ability of insulin to regulate plasma FFA concentrations is impaired in healthy subjects with muscle insulin resistance, indicating that insulin-resistant individuals share defects in the ability of insulin to stimulate muscle glucose disposal and to inhibit adipose tissue lipolysis.     

Sex-related differences in peripheral glucose metabolism in normal subjects

The metabolic response of muscle tissue to glucose ingestion was studied in 10 normal men (M) and women (F) by using the forearm balance technique and indirect calorimetry simultaneously. During the 3 hours after a 75 g--oral glucose load, glucose uptake per unit muscle mass was significantly higher in women than in men, F = 187.3 +/- 26.9 vs M = 116.7 +/- 9.5 mg/100 g forearm muscle (P less than 0.05). A significant difference in muscle glucose fate was also observed since the amount of glucose utilized through a nonoxidative pathway was significantly higher in women, F = 84.5 +/- 2.6% (161.8 +/- 27.3 mg/100 g forearm muscle) vs M = 75.3 +/- 2.2% (87.2 +/- 8.6 mg/100 g forearm muscle) (P less than 0.05), whereas the amount of glucose oxidized in relation to glucose uptake was significantly higher in men, M = 24.7 +/- 2.2% (28.2 +/- 3.2 mg/100 g forearm muscle) vs F = 15.5 +/- 2.6% (27.8 +/- 5.4 mg/100 g forearm muscle) (P less than 0.05). No significant differences in insulin response to glucose ingestion were detected between groups. The women showed greater suppression of serum free fatty acids (FFA) levels in relation to basal levels than men. We conclude that: 1) after ingesting 75 g glucose, normal women showed greater glucose uptake per unit muscle mass than normal men, 2) for 3 hours after the ingestion of 75 g glucose, the predominant tendency toward utilizing glucose by a nonoxidative pathway is more marked in normal women than in normal men, and 3) the higher glucose uptake per unit muscle mass in the female group in the presence of an insulin response not significantly different from that of the male group suggests that muscle insulin sensitivity is greater in normal women.     

Metabolic effects of cortisol in man--studies with somatostatin

The metabolic effects of chronic hypercortisolaemia were studied by administration of tetracosactrin-depot, 1 mg I.M. daily for 36-60 hr to normal subjects. Partial insulin and glucagon deficiency were induced at the end of the period by infusion of somatostatin, 100 micrograms/h for 210 min. Tetracosactrin alone induced a three fold rise in basal serum cortisol levels and fasting blood glucose concentration rose from 5.2 +/- 0.2 to 7.2 +/- 0.2 mmole/l (p less than 0.01) with a rise in fasting serum insulin from 5.2 +/- 1.2 to 13.1 +/- 1.9 mU/l (p less than 0.02). Concentrations of the gluconeogenic precursors lactate, pyruvate and alanine were also raised, but non-esterified fatty acid, glycerol and ketone body levels were unchanged. Somatostatin infusion caused a 30%-50% decrease in serum insulin and a 20%-60% decrease in plasma glucagon concentrations both before and after tetracosactrin administration. A similar rise in blood glucose concentration, relative to the saline control, occurred over the period of somatostatin infusion both with and without elevated cortisol levels. However, prior tetracosactrin administration caused a 100% greater rise in blood ketone body concentrations during infusion of somatostatin than was seen in the euadrenal state, despite similar plasma NEFA concentrations. Hypercortisolaemia causes hyperglycaemia and elevated gluconeogenic precursor concentrations but the associated rise in serum insulin concentrations limits lipolysis and ketosis. In insulin deficiency, a ketotic effort of glucocorticoid excess is evident which may be independent of lipolysis and occurs despite concurrent glucagon deficiency. These catabolic actions of cortisol are likely to be of major importance in the metabolic response to stress.     

Postprandial silent ischaemia following a fatty meal in patients with recently diagnosed coronary artery disease

Silent myocardial ischaemia (SI) is recognised as an important prognostic factor in patients with coronary artery disease (CAD). Postprandial angina is related to severity of CAD. The effect of postprandial metabolic changes in the pathogenesis of SI is unclear. We studied the postprandial changes in glucose, insulin and triglyceride, and non-esterified fatty acids (NEFA) in relation to postprandial SI and exercise capacity, in patients with CAD. Forty elderly volunteers (63 +/- 1 years) mean age +/- s.e.m., with a history of angina were selected on the basis of a Rose questionnaire and a positive exercise stress test (modified Bruce protocol). The test meal contained 45% fat. The meal was consumed at 9.00 am and hourly blood samples were taken for glucose, insulin, triglyceride and NEFA. Continuous Holter monitoring for SI was conducted using a Spacelabs 2000 monitor. Twenty-five percent of the subjects had episodes of silent ischaemia. Postprandial glucose, insulin, triglyceride, and NEFA were not significantly different in the patients with SI (group 1, n = 10) compared with those without SI (group 2, n = 30). The mean exercise time was 6.1 +/- 0.8 min in group 1 compared with 6.8 +/- 0.5 minutes in group 2 (P = 0.48). The time to onset of ST depression during exercise test was also not significantly different in the two groups. The occurrence of postprandial SI cannot be related to changes in plasma levels of glucose, triglyceride, insulin, and NEFA. The explanation is not apparent from this study but may relate to a haemodynamic changes such as mesenteric steal. Journal of Human Hypertension (2000) 14, 391-394     

Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus.

AIMS: The long duration of action of soluble insulin given in the evening could contribute to the high prevalence of nocturnal hypoglycaemia seen in young children with Type 1 diabetes mellitus (T1DM). We examined whether replacing soluble insulin with insulin lispro reduced this risk in children on a three times daily insulin regimen. METHODS: Open crossover study comparing insulin lispro vs. soluble insulin in 23 (16 boys) prepubertal children (age 7-11 years) with T1DM on three injections/day; long-acting isophane insulin remained identical. At the end of each 4-month treatment arm, an overnight 15-min venous sampled blood glucose profile was performed. RESULTS: Despite similar blood glucose levels pre-evening meal (lispro vs. soluble: mean +/- se 6.5 +/- 1.0 vs. 7.1 +/- 1.1 mmol/l, P = 0.5), post-meal (18.00-22.00 h) blood glucose levels were lower on insulin lispro (area under curve 138 +/- 12 vs. 170 +/- 13 mmol min-1 l-1, P = 0.03). In contrast, in the early night (22.00-04.00 h) the prevalence of low blood glucose levels (< 3.5 mmol/l) was lower on lispro (8% of blood glucose levels) than on soluble insulin (13%, P = 0.01). In the early morning (04.00-07.00 h) mean blood glucose and prevalence of low levels were no different between the two treatment groups, and fasting (07.00 h) blood glucose levels were similar (6.1 +/- 0.8 vs. 6.3 +/- 0.9 mmol/l, P = 0.8). At the end of each treatment arm there were no differences in HbA1c (lispro vs. soluble 8.6% vs. 8.4%, P = 0.3), or in insulin doses (mean, range 0.97, 0.68-1.26 vs. 0.96, 0.53-1.22 U/kg per day, P = 0.2). CONCLUSIONS: The shorter duration of action of insulin lispro given before the evening meal may reduce the prevalence of early nocturnal hypoglycaemia without compromising HbA1c in young children with T1DM.     

Impaired plasma nonesterified fatty acid tolerance is an early defect in the natural history of type 2 diabetes

CONTEXT: Abnormal plasma nonesterified fatty acid (NEFA) metabolism may play a role in the development of type 2 diabetes. OBJECTIVES: Our objectives were to demonstrate whether there is a defect in insulin-mediated suppression of plasma NEFA appearance (RaNEFA) and oxidation (OxNEFA) during enhanced intravascular triacylglycerol lipolysis early in the natural history of type 2 diabetes, and if so, to determine whether other mechanisms than reduced insulin-mediated suppression of intracellular lipolysis are involved. DESIGN: These are cross-sectional studies. SETTING: The studies were performed at an academic clinical research center. PARTICIPANTS: Nine healthy subjects with both parents with type 2 diabetes (FH+) and nine healthy subjects with no first-degree relatives with type 2 diabetes (FH-) with similar anthropometric features were included in the studies. INTERVENTIONS: Pancreatic clamps and iv infusion of stable isotopic tracers ([1,1,2,3,3-(2)H5]-glycerol and [U-(13)C]-palmitate or [1,2-(13)C]-acetate) were performed while intravascular triacylglycerol lipolysis was simultaneously clamped by iv infusion of heparin plus Intralipid at low (fasting) and high insulin levels. Oral nicotinic acid (NA) was used to inhibit intracellular lipolysis. MAIN OUTCOME MEASURES: RaNEFA and OxNEFA were determined. RESULTS: During heparin plus Intralipid infusion at high plasma insulin levels, and despite similar intravascular lipolytic rates, FH+ had higher RaNEFA and OxNEFA than FH- (RaNEFA: 17.4+/-6.3 vs. 9.2+/-4.2; OxNEFA: 4.5+/-1.8 vs. 2.3+/-1.5 micromol/kg lean body mass/min), independent of NA intake, gender, age, and body composition. In the presence of NA, insulin-mediated suppression of RaNEFA was still observed in FH-, but not in FH+. CONCLUSIONS: Increased RaNEFA and OxNEFA during intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.     

Contribution of nonesterified fatty acids to insulin resistance in the elderly with normal fasting but diabetic 2-hour postchallenge plasma glucose levels: the Baltimore Longitudinal Study of Aging

Isolated postchallenge hyperglycemia (IPH) with normal fasting plasma glucose <100 mg/dL and plasma glucose with diabetic 2-hour plasma glucose >or=200 mg/dL after an oral glucose tolerance test (OGTT) is a common occurrence in the elderly. We sought to understand what unique characteristics this population might have that puts it at risk for this particular metabolic finding. We therefore conducted a longitudinal study of volunteers in the Baltimore Longitudinal Study of Aging (BLSA). All volunteers had an OGTT performed (75 g) on 2 or more occasions. We measured plasma levels of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, leptin, adiponectin, resistin, C-reactive protein, cytokines, and their soluble receptors, as well as nonesterified free fatty acids (NEFAs). We determined that 22 subjects in BLSA had IPH, accounting for 2.1% of the BLSA population. All 22 were older than 65 years. They were then matched by age, sex, and body mass index to 12 subjects who had isolated impaired glucose tolerance (IGT) and 15 subjects with normal glucose tolerance (NGT). All subjects had normal fasting glucose levels <100 mg/dL in accordance with the American Diabetes Association Expert Committee on the Classification and Diagnosis of Diabetes Mellitus criteria (2003). We found that subjects with IPH had similar plasma insulin levels to the other 2 groups, except at the 2-hour time when their insulin levels were higher than NGT (P < .05). Although there was a clear trend for differences in the insulinogenic index, the areas under the curves for insulin, systolic blood pressure, adiponectin, and C-reactive protein across the glucose tolerance categories revealed no statistical significance. Cytokines and their soluble receptors, gut hormones, and adipokines were similar in all 3 groups. The NEFA levels were significantly elevated in the fasting state (P < .05) in the IPH compared with NGT, with IGT intermediate between the other 2 groups. The rate of clearance of NEFAs after the OGTT decreased progressively from the NGT to the IPH group (in micromoles per liter per minute: NGT, 11.9 vs IGT, 7.6 vs IPH, 3.0). We conclude that the rate of suppression of lipolysis in the elderly determines the sensitivity of glucose uptake to insulin after OGTT.     

Impaired glucose tolerance is characterized by multiple abnormalities in the regulation of intermediary metabolism.

The responses of circulating intermediary metabolites to a low-dose sequential insulin infusion (basal, 0.005, 0.01, and 0.05 U kg-1 h-1) were assessed in eight non-obese men with Impaired Glucose Tolerance (IGT), and in eight healthy control subjects with normal glucose tolerance matched for age, gender, and body mass index. Fasting hyperinsulinaemia was observed in the subjects with IGT (7.4 +/- 1.0 vs 2.9 +/- 0.3 mU I-1, p less than 0.001). While there was no significant difference (p greater than 0.1) in fasting venous glucose levels between the groups, fasting concentrations of lactate (p less than 0.02), alanine (p less than 0.01), and glycerol (p less than 0.05) were significantly elevated in the subjects with IGT. During the incremental insulin infusion, overall concentrations of glucose (p less than 0.05), lactate (p less than 0.05), alanine (p less than 0.05), glycerol (p less than 0.05), immunoreactive insulin (p less than 0.001), and C-peptide (p less than 0.01) were significantly higher in the subjects with IGT. Linear dose-response relationships (p less than 0.005) for circulating immunoreactive insulin (log) vs metabolite concentrations were demonstrated by analysis of variance for glucose, non-esterified fatty acids (NEFA), glycerol, and total ketone bodies. For glucose, glycerol, and NEFA, group dose-response regression lines for the subjects with IGT were displaced significantly to the right (p less than 0.001 for each) of those for the normal control subjects, implying insulin insensitivity. In addition to the recognized defect in glucose homeostasis, these results indicate impaired regulation of multiple aspects of intermediary metabolism including lipolysis in IGT.