Three months energy restricted diet does not reduce peripheral insulin resistance in newly diagnosed non insulin dependent diabetics

Sixteen newly diagnosed non insulin dependent diabetic patients were treated for 3 months with an individual energy restricted diet. The effect on weight, hyperglycaemia and insulin response to oral glucose was measured in all subjects, and in 7, peripheral insulin resistance was estimated using a hyperinsulinaemic glucose clamp at two insulin infusion rates (40 and 400 mU m-2 X min-1). After diet, fasting plasma glucose fell from 12.0 +/- 0.7 mmol/l (mean +/- SEM) to 7.4 +/- 0.5 mmol/l (P less than 0.001) and weight fell from 92.9 +/- 4.2 kg to 85.0 +/- 3.1 kg (P less than 0.001). The plasma insulin response to oral glucose was unchanged after diet therapy. Insulin induced glucose disposal (M) was also unaffected by diet at insulin infusion rates of 40 mU m-2 X min-1 (12.5 +/- 1.5 mumol X kg-1 X min-1 vs 15.7 +/- 1.6 mumol X kg-1 X min-1) and 400 mU m-2 X min-1 (49.5 +/- 2.7 mumol X kg-1 X min-1 vs 55.1 +/- 2.5 mumol X kg-1 X min-1). These results show that 3 months reduction of energy consumption with weight loss in newly diagnosed non insulin dependent diabetics improves B-cell responsiveness to glucose but has no effect on liver glucose output or on peripheral insulin action.     

Brittle diabetes: long-term control with a portable,continuous, intravenous insulin infusion system.

A young woman had severe brittle diabetes mellitus that was critically unmanageable with all conventional insulin treatment. Continuous subcutaneous and intramuscular infusions of insulin also failed to control her metabolic instability. Use of a continuous intravenous infusion, however, whereby a portable, variable-rate, battery-operated syringe pump delivered insulin through a subcutaneously tunnelled central venous catheter, resulted in good control. When she was receiving hourly intramuscular insulin injections (a mean of 778 IU daily) mean blood glucose concentrations had been 22.1 +/- 1.4 mmol/l (398 +/- 25 mg/100 microliters). After she had received the intravenous infusion for one month as an outpatient mean blood glucose concentration was 8.2 +/- 0.46 mmol/l (148 +/- 8 mg/100 microliters) and only 80 IU insulin daily was required. Follow-up after over five months of use showed that few complications had occurred. The system is simple to use and safe, and the diabetes had been stabilised such that she could enjoy a near-normal life style.     

Estimations of muscle interstitial insulin, glucose, and lactate in type 2 diabetic subjects

Previous measurement of insulin in human muscle has shown that interstitial muscle insulin and glucose concentrations are approximately 30-50% lower than in plasma during hyperinsulinemia in normal subjects. The aims of this study were to measure interstitial muscle insulin and glucose in patients with type 2 diabetes to evaluate whether transcapillary transport is part of the peripheral insulin resistance. Ten patients with type 2 diabetes and ten healthy controls matched for sex, age, and body mass index were investigated. Plasma and interstitial insulin, glucose, and lactate (measured by intramuscular in situ-calibrated microdialysis) in the medial quadriceps femoris muscle were analyzed during a hyperinsulinemic euglycemic clamp. Blood flow in the contralateral calf was measured by vein plethysmography. At steady-state clamping, at 60-120 min, the interstitial insulin concentration was significantly lower than arterial insulin in both groups (409 +/- 86 vs. 1,071 +/- 99 pmol/l, P < 0.05, in controls and 584 +/- 165 vs. 1, 253 +/- 82 pmol/l, P < 0.05, in diabetic subjects, respectively). Interstitial insulin concentrations did not differ significantly between diabetic subjects and controls. Leg blood flow was significantly higher in controls (8.1 +/- 1.2 vs. 4.4 +/- 0.7 ml. 100 g(-1).min(-1) in diabetics, P < 0.05). Calculated glucose uptake was less in diabetic patients compared with controls (7.0 +/- 1.2 vs. 10.8 +/- 1.2 micromol. 100 g(-1).min(-1), P < 0.05, respectively). Arterial and interstitial lactate concentrations were both higher in the control group (1.7 +/- 0.1 vs. 1.2 +/- 0.1, P < 0. 01, and 1.8 +/- 0.1 vs. 1.2 +/- 0.2 mmol/l, P < 0.05, in controls and diabetics, respectively). We conclude that, during hyperinsulinemia, muscle interstitial insulin and glucose concentrations did not differ between patients with type 2 diabetes and healthy controls despite a significantly lower leg blood flow in diabetic subjects. It is suggested that decreased glucose uptake in type 2 diabetes is caused by insulin resistance at the cellular level rather than by a deficient access of insulin and glucose surrounding the muscle cell.     

Dissociation between metabolic and vascular insulin resistance in aging

Physiological actions of insulin via activation of the phosphatidylinositol 3-kinase/Akt pathway in the endothelium serve to couple regulation of hemodynamic and metabolic homeostasis. Insulin resistance, endothelial dysfunction, and hypertension increase in prevalence with aging. We investigated the metabolic and endothelial actions of insulin in 24- vs. 3-mo Sprague-Dawley rats. With the use of the hyperinsulinemic euglycemic clamp, the rate of glucose infusion necessary to maintain equivalent plasma glucose (5.5 mmol/l) was similar in 24- vs. 3-mo rats, as was fasting glucose (5.2 +/- 0.33 vs. 4.4 +/- 0.37 mmol/l; mean +/- SE) and insulin (0.862 +/- 0.193 vs. 1.307 +/- 0.230 mg/l). Systolic blood pressure was higher in 24-mo rats (133 +/- 5 vs. 110 +/- 4 mmHg; P = 0.005). Endothelial nitric oxide (NO)-dependent relaxation to insulin was impaired in aortas of 24- vs. 3-mo rats (maximal response 8.9 +/- 4.3 vs. 34.9 +/- 3.9%; P = 0.002); N(G)-nitro-l-arginine methyl ester abolished insulin-mediated relaxation in 3- but not 24-mo rats. Endothelium NO-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation, as well as NADPH oxidase activity, were similar in 3- and 24-mo rats. Insulin increased aortic serine phosphorylation of Akt in 3-mo rats by 120% over 24-mo rats (P < 0.05) and serine phosphorylation of endothelial NO synthase (eNOS) in 3-mo rats by 380% over 24-mo rats (P < 0.05). Aortic expression of phosphorylated c-Jun NH(2)-terminal kinase-1 and serine phosphorylated insulin receptor substrate-1, known mediators of metabolic insulin resistance, was similar in 3- and 24-mo rats. Expression of caveolin-1, a regulator of eNOS activity and insulin signaling, was 55% lower in 24- than 3-mo rats (P = 0.002). In summary, impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin-mediated activation of the Akt/eNOS pathway, but intact activation of the acetylcholine-mediated Ca(2+)-calmodulin/eNOS pathway. Vascular insulin resistance in aging may add to the increased susceptibility of this population to vascular injury induced by traditional cardiovascular risk factors.     

Effect of near physiologic insulin therapy on hypoglycemia counterregulation in type-1 diabetes

OBJECTIVES: The aim of this study was to examine hormonal counterregulation during insulin-induced hypoglycemia in type-1 diabetic patients during long-term near normoglycemic insulin therapy and intensive clinical care. METHODS: Type-1 diabetic patients (age 35.3 +/- 2 years, body mass index 22.8 +/- 1 kg x m(-2), mean diabetes duration 13.6 (11-17 years), mean HbA1c during the last year 6.6 +/- 0.1%) and nondiabetic subjects were studied during (0-120 min) and after (120-240 min) hypoglycemic (3.05 mmol/l) hyperinsulinemic (approximately 330 pmol/l) clamp tests. RESULTS: During hypoglycemia peak plasma concentrations of glucagon (199 +/- 16 vs. 155 +/- 11 ng/l, p < 0.05), epinephrine (4,514 +/- 644 vs. 1,676 +/- 513 pmol/l, p < 0.001), norepinephrine (2.21 +/- 0.14 vs. 1.35 +/- 0.19 nmol/l, p < 0.01) and cortisol (532 +/- 44 vs. 334 +/- 61 nmol/l) were reduced in the diabetic patients. Plasma lactate did not change from baseline values (0.51 +/- 0.06 mmol/l) in diabetic but doubled in healthy subjects (1.13 +/- 0.111 mmol/l, p < 0.001 vs. control). During the posthypoglycemic recovery period plasma concentrations of free fatty acids were higher in diabetic patients at 240 min (1.34 +/- 0.12 vs. 2.01 +/- 0.23 mmol/l, p < 0.05). CONCLUSION: Despite long-term near physiologic insulin substitution and the low incidence of hypoglycemia, hormonal hypoglycemia counterregulation was impaired in type-1 diabetic patients after a diabetes duration of more than 10 years.     

Impaired non-esterified fatty acid suppression is associated with endothelial dysfunction in insulin resistant subjects.

In a recent study, we found a significant association between insulin resistance (IR) and disturbed flow-associated (endothelial-dependent) vasodilation in first-degree relatives of subjects with type 2 diabetes. However, the mechanisms linking insulin resistance and endothelial dysfunction (ED) have not been fully elucidated. Experimental data have pointed out that non-esterified fatty acids (NEFA) have a modulating effect on NO-synthase activity, and therefore on endothelial function. The aim of our study was to evaluate whether insulin resistance associated impaired NEFA suppression is present in subjects with ED. We examined 53 first-degree relatives (FDR) of patients with type 2 diabetes (32f, 21 m, mean age 35 years). Endothelial function was measured as flow-associated vasodilation (FAD%) of the brachial artery. Insulin sensitivity was evaluated with a standard hyperinsulinemic glucose clamp (insulin infusion rate of 1 mU/kg/min). While under fasting conditions, NEFA did not differ between groups with high or low FAD (0.415+/-0.033 vs. 0.394 +/- 0.040 mmol/l; p = n. s.), reduced FAD% was significantly associated with higher non-esterified fatty acids concentrations during steady state of the glucose clamp (0.072+/-0.022 vs. 0.039+/-0.016mmol/l; p=0.04). This association was independent of insulin levels under fasting conditions and during the glucose clamp. In conclusion, our results reveal a significant association between endothelial dysfunction and impaired non-esterified fatty acid suppression in insulin resistant subjects. As insulin resistance of lipolysis is a feature of the insulin resistance syndrome, these results suggest that elevated NEFA concentrations could play a role linking endothelial dysfunction and insulin resistance in vivo.     

Effects of treadmill exercise to exhaustion on the insulin response to hyperglycemia in untrained men

The effects of a single bout of exercise to exhaustion on pancreatic insulin secretion were determined in seven untrained men by use of a 3-h hyperglycemic clamp with plasma glucose maintained at 180 mg/100 ml. Clamps were performed either 12 h after an intermittent treadmill run at approximately 77% maximum O2 consumption or without prior exercise. Arterialized blood samples for glucose, insulin, and C-peptide determination were obtained from a heated hand vein. The peak insulin response during the early phase (0-10 min) of the postexercise clamp was higher (81 +/- 8 vs. 59 +/- 9 microU/ml; P less than 0.05) than in the nonexercise clamp. Incremental areas under the insulin (376 +/- 33 vs. 245 +/- 51 microU.ml-1.min) and C-peptide (17 +/- 2 vs. 12 +/- 1 ng.ml-1.min) curves were also greater (P less than 0.05) during the early phase of the postexercise clamp. No differences were observed in either insulin concentrations or whole body glucose disposal during the late phase (15-180 min). Area under the C-peptide curve was greater during the late phase of the postexercise clamp (650 +/- 53 vs. 536 +/- 76 ng.ml-1.min, P less than 0.05). The exercise bout induced muscle soreness and caused an elevation in plasma creatine kinase activity (142 +/- 32 vs. 305 +/- 31 IU/l; P less than 0.05) before the postexercise clamp. We conclude that in untrained men a bout of running to exhaustion increased pancreatic beta-cell insulin secretion during the early phase of the hyperglycemic clamp. Increased insulin secretion during the late phase of the clamp appeared to be compensated by increased insulin clearance.     

Sulfonylurea therapy fails to diminish insulin resistance in type I-diabetic subjects

To assess whether extrapancreatic effects of sulfonylureas in vivo are detectable in the absence of endogenous insulin secretion, insulin sensitivity was determined in six insulin-deficient type 1-diabetic subjects. Peripheral uptake and hepatic production of glucose and lipolysis were measured during hyperinsulinemia using the euglycemic clamp technique and 3-3H-glucose infusions twice, once during a period with glibornuride treatment (50 mg b.i.d.), and once without. Hepatic glucose production decreased in diabetic subjects during hyperinsulinemia (insulin infusion of 20 mU/m2 X min; plasma free insulin levels of 40 +/- 4 mU/l) from 2.9 +/- 0.6 mg/kg min to 0.2 +/- 0.1 mg/kg X min after 120 min, and plasma free fatty acid (FFA) concentrations decreased from 1.33 +/- 0.29 to 0.38 +/- 0.08 mmol/l. Hepatic production, peripheral uptake of glucose and plasma FFA concentrations before and during hyperinsulinemia were not influenced by pretreatment with glibornuride. Compared to 8 non-diabetic subjects, type 1-diabetics demonstrated a diminished effect of hyperinsulinemia on peripheral glucose clearance (2.4 +/- 0.04 vs 4.2 +/- 0.5 ml/kg X min, P less than 0.01), whereas hepatic glucose production and plasma FFA levels were similarly suppressed by insulin. The data indicate that sulfonylurea treatment did not improve the diminished insulin sensitivity of peripheral glucose clearance in type 1-diabetic subjects; insulin action on hepatic glucose production and lipolysis was unimpaired in diabetics and remained uninfluenced by glibornuride. Thus, extrapancreatic effects of sulfonylureas in vivo are dependent on the presence of functioning beta-cells.     

Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans

To investigate the effect of elevated plasma free fatty acid (FFA) concentrations on splanchnic glucose uptake (SGU), we measured SGU in nine healthy subjects (age, 44 +/- 4 yr; body mass index, 27.4 +/- 1.2 kg/m(2); fasting plasma glucose, 5.2 +/- 0.1 mmol/l) during an Intralipid-heparin (LIP) infusion and during a saline (Sal) infusion. SGU was estimated by the oral glucose load (OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin (100 mU x m(-2) x min(-1)) clamp, and a 75-g OGL was ingested 3 h after the insulin clamp was started. After glucose ingestion, the steady-state glucose infusion rate (GIR) during the insulin clamp was decreased to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the period after glucose ingestion from the ingested glucose load. [3-(3)H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of endogenous glucose production (EGP) and glucose disappearance (R(d)). During the 3-h euglycemic insulin clamp before glucose ingestion, R(d) was decreased (8.8 +/- 0.5 vs. 7.6 +/- 0.5 mg x kg(-1) x min(-1), P < 0.01), and suppression of EGP was impaired (0.2 +/- 0.04 vs. 0.07 +/- 0.03 mg x kg(-1) x min(-1), P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly increased during the LIP vs. Sal infusion study (30 +/- 2 vs. 20 +/- 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose R(d) and insulin-mediated suppression of EGP in healthy subjects but augments SGU.     

The relationship between glycemia, insulin and oxidative stress in hereditary hypertriglyceridemic rat

The aim of this study was to determine the effects of insulin infusion on oxidative stress induced by acute changes in glycemia in non-stressed hereditary hypertriglyceridemic rats (hHTG) and Wistar (control) rats. Rats were treated with glucose and either insulin or normal saline infusion for 3 hours followed by 90 min of hyperglycemic (12 mmol/l) and 90 min of euglycemic (6 mmol/l) clamp. Levels of total glutathione (GSH), oxidized glutathione (GSSG) and total antioxidant capacity (AOC) were determined to assess oxidative stress. In steady states of each clamp, glucose infusion rate (GIR) was calculated for evaluation of insulin sensitivity. GIR (mg.kg(-1).min(-1)) was significantly lower in hHTG in comparison with Wistar rats; 25.46 (23.41 - 28.45) vs. 36.30 (27.49 - 50.42) on glycemia 6 mmol/l and 57.18 (50.78 - 60.63) vs. 68.00 (63.61 - 85.92) on glycemia 12 mmol/l. GSH/GSSG ratios were significantly higher in hHTG rats at basal conditions. Further results showed that, unlike in Wistar rats, insulin infusion significantly increases GSH/GSSG ratios in hHTG rats: 10.02 (9.90 - 11.42) vs. 6.01 (5.83 - 6.43) on glycemia 6 mmol/l and 7.42 (7.15 - 7.89) vs. 6.16 (5.74 - 7.05) on glycemia 12 mmol/l. Insulin infusion thus positively influences GSH/GSSG ratio and that way reduces intracellular oxidative stress in insulin-resistant animals.     

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

Apelin is the endogenous ligand of the G-protein coupled apj receptor. Apelin is expressed in the brain, the hypothalamus and the stomach and was recently shown also to be an adipokine secreted from the adipocytes. Although apelin has been suggested to be involved in the regulation of food intake, it is not known whether the peptide affects islet function and glucose homeostasis. We show here that the apj receptor is expressed in pancreatic islets and that intravenous administration of full-length apelin-36 (2 nmol/kg) inhibits the rapid insulin response to intravenous glucose (1 g/kg) by 35% in C57BL/6J mice. Thus, the acute (1-5 min) insulin response to intravenous glucose was 682+/-23 pmol/l after glucose alone (n=17) and 445+/-58 pmol/l after glucose plus apelin-36 (n=18; P=0.017). This was associated with impaired glucose elimination (the 5-20 min glucose elimination was 2.9+/-0.1%/min after glucose alone versus 2.3+/-0.2%/min after glucose plus apelin-36, P=0.008). Apelin (2 nmol/kg) also inhibited the insulin response to intravenous glucose in obese insulin resistant high-fat fed C57BL/6J mice (P=0.041). After 60 min incubation of isolated islets from normal mice, insulin secretion in the presence of 16.7 mmol/l glucose was inhibited by apelin-36 at 1 mumol/l, whereas apelin-36 did not significantly affect insulin secretion at 2.8 or 8.3 mmol/l glucose or after stimulation of insulin secretion by KCl. Islet glucose oxidation at 16.7 mmol/l was not affected by apelin-36. We conclude that the apj receptor is expressed in pancreatic islets and that apelin-36 inhibits glucose-stimulated insulin secretion both in vivo and in vitro. This may suggest that the islet beta-cells are targets for apelin-36.     

Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes.

The role of preserved beta-cell function in preventing ketoacidosis in type I insulin-dependent diabetes was assessed in eight patients with and seven patients without residual beta-cell function as determined from C-peptide concentrations. After 12 hours of insulin fatty-acid, and glycerol concentrations were all significantly higher in patients without beta-cell function than in those with residual secretion. Mean blood glucose concentrations reached 17.2 +/- SE of mean 1.3 mmol/l (310 +/- 23 mg/100 ml) in the first group compared with 8.8 +/- 1.4 mmol/l (159 +/- 25 mg/100 ml) in the second (P less than 0.01), while 3-hydroxybutyrate concentrations rose to 5.5 +/- mmol/l (57 +/- 5 mg/100 ml) and 1.4 +/- 0.3 mmol/l (15 +/- 3 mg/100 ml) in the two groups respectively (P less than 0.01). Individual mean C-peptide concentrations showed a significant inverse correlation with the final blood glucose values (r = -0.91; P less than 0.02). These findings strongly suggest that even minimal residual insulin secretion is important for metabolic wellbeing in diabetes and may prevent the development of severe ketoacidosis when insulin delivery is inadequate.     

Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes

We determined whether insulin therapy changes liver fat content (LFAT) or hepatic insulin sensitivity in type 2 diabetes. Fourteen patients with type 2 diabetes (age 51+/-2 yr, body mass index 33.1+/-1.4 kg/m2) treated with metformin alone received additional basal insulin for 7 mo. Liver fat (proton magnetic resonance spectroscopy), fat distribution (MRI), fat-free and fat mass, and whole body and hepatic insulin sensitivity (6-h euglycemic hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose) were measured. The insulin dose averaged 75+/-10 IU/day (0.69+/-0.08 IU/kg, range 24-132 IU/day). Glycosylated hemoglobin A1c (Hb A1c) decreased from 8.9+/-0.3 to 7.4+/-0.2% (P<0.001). Whole body insulin sensitivity increased from 2.21+/-0.38 to 3.08+/-0.40 mg/kg fat-free mass (FFM).min (P<0.05). This improvement could be attributed to enhanced suppression of hepatic glucose production (HGP) by insulin (HGP 1.04+/-0.28 vs. 0.21+/-0.19 mg/kg FFM.min, P<0.01). The percent suppression of HGP by insulin increased from 72+/-8 to 105+/-11% (P<0.01). LFAT decreased from 17+/-3 to 14+/-3% (P<0.05). The change in LFAT was significantly correlated with that in hepatic insulin sensitivity (r=0.56, P<0.05). Body weight increased by 3.0+/-1.1 kg (P<0.05). Of this, 83% was due to an increase in fat-free mass (P<0.01). Fat distribution and serum adiponectin concentrations remained unchanged while serum free fatty acids decreased significantly. Conclusions: insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.     

Intermediate acting insulin given at bedtime: effect on blood glucose concentrations before and after breakfast.

Six C-peptide deficient diabetics receiving twice daily mixtures of short and intermediate acting insulins were selected for study because of persistently raised blood glucose concentrations before and after breakfast. They were investigated to assess the effect of moving their evening injection of intermediate acting insulin to bedtime. The patients'' usual twice daily insulin treatment was optimised and compared with the bedtime regimen during inpatient metabolic studies and an outpatient crossover study. With the conventional injection regimen blood glucose concentration rose sharply from 0500 to reach a fasting mean value of 10 +/- SE 1 . 6 mmol/l (180 +/- 29 mg/100 ml) and 16 . 8 +/- 2 . 2 mmol/l (303 +/- 40 mg/100 ml) after breakfast. By contrast, when the evening dose of intermediate acting insulin was delayed until bedtime the nocturnal rise in blood glucose concentration started later and was significantly lower both fasting (7 . 5 +/- 1 . 1 mmol/l (135 +/- 20 mg/100 ml); p less than 0 . 02) and after breakfast (13 . 2 +/- 1 . 4 mmol/l(238 +/- 25 mg/100 ml); p less than 0 . 02). Fasting blood concentrations of ketone bodies (3-hydroxybutyrate) were also significantly decreased. Plasma free insulin concentrations showed the predicted changes in five of the six patients. Blood glucose profiles collected over four months during the outpatient study confirmed the beneficial effect of giving intermediate acting insulin at bedtime.     

Management of severely brittle diabetes by continuous subcutaneous and intramuscular insulin infusions: evidence for a defect in subcutaneous insulin absorption.

Severely brittle diabetes is defined as a rare subtype of insulin-dependent diabetes with wide, fast, unpredictable, and inexplicable swings in blood glucose concentration, often culminating in ketoacidosis or hypoglycaemic coma. To assess the role of inappropriate type, amount, or timing of insulin treatment and the route of administration as a cause of severe brittleness six patients with continuous subcutaneous insulin infusion, which provides a high degree of optimisation of dosage with exogenous insulin in stable diabetics. The glycaemic control achieved during continuous subcutaneous insulin infusion was compared with that during continuous intramuscular insulin infusion. Six patients with non-brittle diabetes were also treated by continuous subcutaneous insulin infusion. These patients achieved the expected improvement in glycaemic control (mean +/- SD plasma glucose concentration 5.1 +/- 2.3 mmol/l (92 +/- 41 mg/100 ml)), but not the patients with brittle diabetes remained uncontrolled with continuous subcutaneous infusion (13.6 +/- 5.8 mmol/1 (245 +/- 105 mg/100 ml) compared with 10.3 +/- 4.1 mmol/l (186 +/- 74 mg/100 ml) during treatment with optimised conventional subcutaneous injections). During continuous intramuscular infusion, however, glycaemic control in five of the patients with brittle diabetes was significantly improved (7.7 +/- 2.6 mmol/l (139 +/- 47 mg/100 ml). The remaining patient with brittle diabetes, previously safely controlled only with continuous intravenous insulin, did not respond to continuous intramuscular infusion. It is concluded that in five of the six patients with brittle diabetes studied here impaired or irregular absorption of insulin from the subcutaneous site played a more important part in their hyperlability than inappropriate injection strategies. This absorption defect was presumably bypassed by the intramuscular route.     

Venous versus arterialised venous blood for assessment of blood glucose levels during glucose clamping: comparison in healthy men.

The aim of this study was to investigate the influence of the arteriovenous (A-V) gradient in blood glucose concentrations at low and high insulin levels on the determination of glucose requirements during glucose clamping in 9 healthy, insulin sensitive, male volunteers. In a random order two clamps were performed, once using arterialised venous blood (A Clamp, mean pO2 = 11.5 +/- 0.36 kPa, 86 +/- 2.7 mmHg), and once using venous blood (V clamp, mean pO2 = 7.9 +/- 0.21 kPa, 59 +/- 1.6 mmHg). Insulin levels were maintained at 48 +/- 2.4 mU/l from 0-180 min and at 1054 +/- 114 mU/l from 180-360 min. Elevation of insulin levels caused a significant rise of the A-V gradient: from 0.3 +/- 0.1 to 0.5 +/- 0.1 mmol/l (p < 0.05) and from 0.2 +/- 0.1 to 0.3 +/- 0.1 mmol/l (p < 0.05) during the A and V clamps, respectively. Despite these A-V glucose gradients no significant differences were found for the glucose requirements during the last 30 min of each period of insulin infusion between the A and V clamps: 43.70 +/- 3.4 vs 44.8 +/- 2.8 mumol.kg-1.min-1 during the low insulin level and 77.3 +/- 5.0 vs 76.2 +/- 3.4 mumol.kg-1.min-1 during the high insulin level. We conclude that the A-V glucose gradient, even at high insulin levels, does not influence the assessment of glucose requirements to a measurable extent, allowing the use of the simpler technique of taking venous rather than arterialised venous blood for the measurements of glucose levels during glucose clamping.     

The effects of surgically removing subcutaneous fat on the metabolic profile and insulin sensitivity in obese women after large-volume liposuction treatment.

The aim of this study was to identify the effects of surgically removing subcutaneous fat on the metabolic profile and insulin sensitivity in obese women after large-volume liposuction treatment. An open clinical trial with a non-intervention parallel group was carried out on 12 young, obese women. After randomization, six volunteers were selected to the surgical intervention consisting of large-volume liposuction; the other six women were considered as the non-intervention group. Metabolic profiles and insulin tolerance tests to assess insulin sensitivity were performed on all volunteers before intervention or non-intervention and 21 - 28 days afterwards. There were a significant decrease in glucose (4.9 +/- 0.4 vs. 4.6 +/- 0.2 mmol/l, p < 0.05) and uric acid (250.8 +/- 56.2 vs. 224.0 +/- 53.4 micromol/l, p < 0.05) levels after liposuction; insulin sensitivity improved after the surgical intervention (4.3 +/- 0.9 vs. 5.3 +/- 0.8 %/min, p = 0.046). In conclusion, surgical removal of subcutaneous fat by large-volume liposuction led to an improvement in insulin sensitivity and a decrease in glucose and uric acid concentrations.     

A portable, pre-programmable insulin infusion system in diabetes mellitus.

A miniaturized portable pump has been developed in order to study the effects of pre-programmed insulin infusion patterns on the blood glucose levels in juvenile-onset, insulin-requiring diabetics. Six diabetics undergoing 7 insulin infusion periods of up to 4 days were studied. The mean blood glucose was 7.0 +/- 2.3 (SD) mmol/l and the mean amplitude of glycemic excursions was 5.0 +/- 1.4 mmol/l. Success in achieving normoglycemia will depend on choosing the correct dose of insulin for infusion.     

Loss of entrainment of high-frequency plasma insulin oscillations in type 2 diabetes is likely a glucose-specific beta-cell defect

Spontaneous high-frequency insulin oscillations are easily entrainable to exogenous glucose in vitro and in vivo, but this property is lost in type 2 diabetes (2-DM). We hypothesized that this lack of entrainment in 2-DM would be specific to glucose. This was tested in nine control and ten 2-DM subjects. Serial blood sampling at 1-min intervals was carried out for 60 min in the basal state and for 120 min while small (1-60 mg/kg) boluses of arginine were injected intravenously at exactly 29-min intervals. Samples were analyzed for insulin concentrations, and time series analysis was carried out using spectral analysis. In control subjects, the mean period of basal plasma insulin oscillations was 10.3 +/- 1.3 min and was entrained by arginine to a mean period of 14.9 +/- 0.6 min (P < 0.00001 vs. basal). Similarly, in 2-DM subjects, spontaneous insulin oscillations were entrained by arginine; mean basal insulin period was 10.0 +/- 1.0 min and 14.5 +/- 1.8 min with arginine boluses (P < 0.00001). All of the primary peaks observed in spectral analysis were statistically significant (P < 0.05). Percent total power of primary peaks ranged from 17 to 68%. Thus arginine boluses entrain spontaneous high-frequency insulin oscillations in 2-DM subjects. This represents a distinct and striking difference from the resistance of the beta-cell to glucose entrainment in 2-DM. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in 2-DM is likely a glucose-specific manifestation of beta-cell secretory dysfunction.     

Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 action

The insulinotropic intestinal hormone GLP-1 is thought to exert one of its effects by direct action on the pancreatic beta-cell receptors. GLP-1 is rapidly degraded in plasma, such that only a small amount of the active form reaches the pancreas, making it questionable whether this amount is sufficient to produce a direct incretin effect. The aim of our study was to assess, in a dog model, the putative incretin action of GLP-1 acting directly on the beta-cell in the context of postprandial rises in GLP-1 and glucose. Conscious dogs were fed a high-fat, high-carbohydrate meal, and insulin response was measured. We also infused systemic glucose plus GLP-1, or glucose alone, to simulate the meal test values of these variables and measured insulin response. The results were as follows: during the meal, we measured a robust insulin response (52 +/- 9 to 136 +/- 14 pmol/l, P < 0.05 vs. basal) with increases in portal glucose and GLP-1 but only limited increases in systemic glucose (5.3 +/- 0.1 to 5.7 +/- 0.1 mmol/l, P = 0.1 vs. basal) and GLP-1 (6 +/- 0 to 9 +/- 1 pmol/l, P = 0.5 vs. basal). Exogenous infusion of systemic glucose and GLP-1 produced a moderate increase in insulin (43 +/- 5 to 84 +/- 15 pmol/l, 43% of the meal insulin). However, infusion of glucose alone, without GLP-1, produced a similar insulin response (37 +/- 6 to 82 +/- 14 pmol, 53% of the meal insulin, P = 0.7 vs. glucose and GLP-1 infusion). In conclusion, in dogs with postprandial rises in systemic glucose and GLP-1, the hormone might not have a direct insulinotropic effect and could regulate glycemia via indirect, portohepatic-initiated neural mechanisms.