Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine.

AIMS: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add-on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D). METHODS: This was a 6-month randomized crossover trial comparing add-on insulin detemir versus glargine in poorly controlled T2D with macroangiopathy. At baseline, crossover (3 months) and study end (6 months), we measured HbA1c, EPCs, circulating endothelial cells (CECs), VCAM-1, ICAM-1 and E-selectin. Body weight and hypoglycaemic episodes were also recorded. RESULTS: Forty-two patients completed the study, randomly assigned to the glargine-detemir (n = 21) or the detemir-glargine (n = 21) schedule. At crossover, EPC levels did not change compared with baseline, but significantly increased at study end. CECs decreased over time and were significantly reduced at study end. ICAM-1, VCAM-1 and E-selectin were significantly reduced at crossover and further decreased at study end. No differences were seen in these effects between detemir and glargine. HbA1c showed a carryover effect and its reduction was similar with detemir and glargine in the first arm. Incidence of hypoglycaemia and weight gain was lower with detemir than with glargine in both arms. CONCLUSION: Optimized glycaemic control by add-on basal insulin improved indexes of endothelial damage and regeneration. Compared to glargine, detemir achieved similar endothelial protection with lower weight gain and less hypoglycaemia. These results might have implications for therapy of aging T2D patients with cardiovascular disease.

Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes.

BACKGROUND AND AIMS: Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross-sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients. METHODS AND RESULTS: Common carotid artery intima-media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p<0.05) as compared to those with cIMT < 1 mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits. CONCLUSION: In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications.

Cerebrovascular disease in diabetes mellitus: the role of carotid intima-media thickness.

BACKGROUND AND PURPOSE: Cerebrovascular disease in diabetes appears to be less considered than coronary and peripheral disease, the reason being the intrinsic difficulty in finding available diagnostic tools for its early identification. Among these, carotid artery intima-media thickness (cIMT) represents the simplest measurable parameter for pre-atherosclerotic lesions in extra-cranic arteries. METHODS: The role of cIMT as a surrogate marker of cerebral atherosclerosis and predictor of stroke, its relationship to microangiopathy and chronic inflammation, along with its role as an outcome parameter in anti-hyperglycemic therapeutical intervention trials in type 2 and 1 diabetes mellitus are discussed in this paper. RESULTS AND CONCLUSIONS: Carotid IMT is increased in diabetes. It is an independent predictor of stroke, in particular of the ischemic subtype, and of stroke recurrence in diabetic, as well as in non-diabetic populations. A possible role of cIMT as a predictor of microangiopathy has also been suggested, but it needs further investigation. A weak association with chronic inflammation has been demonstrated in diabetic patients. Carotid IMT has been successfully employed as an outcome parameter for several anti-hyperglycemic therapeutic trials. However data on cIMT as a predictor of cerebrovascular disease are scarce in diabetic patients, particularly in type 1 diabetes, and more studies are needed to define the risk of cerebrovascular disease in diabetic patients.

Hepatic lipid metabolism and non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized pathology with a high prevalence and a possible evolution to its inflammatory counterpart (non-alcoholic steatohepatitis, or NASH). The pathophysiology of NAFLD and NASH has many links with the metabolic syndrome, sharing a causative factor in insulin resistance. According to a two-hit hypothesis, increased intrahepatic triglyceride accumulation (due to increased synthesis, decreased export, or both) is followed by a second step (or "hit"), which may lead to NASH. The latter likely involves oxidative stress, cytochrome P450 activation, lipid peroxidation, increased inflammatory cytokine production, activation of hepatic stellate cells and apoptosis. However, both "hits" may be caused by the same factors. The aim of this article is to overview the biochemical steps of fat regulation in the liver and the alterations occurring in the pathogenesis of NAFLD and NASH.

In Type 1 diabetic patients with good glycaemic control, blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine.

AIMS: The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross-over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end-point was glucose variability. METHODS: Thirty-nine patients [38.1 +/- 9.3 years old (mean +/- sd), diabetes duration 16.6 +/- 8.2 years, glycated haemoglobin (HbA(1c)) 7.6 +/- 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end-points we analysed blood glucose profile, HbA(1c), number of episodes of hypo- and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. RESULTS: During CSII, glucose variability was 5-12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA(1c) was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. CONCLUSIONS: During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.

The metabolic syndrome, diabetes and lung dysfunction.

Sleep-disordered breathing and sleep apnoea are conditions frequently associated with comorbidity, including obesity, diabetes, hypertension, insulin resistance (metabolic syndrome) and cardiovascular disease. The diabetic state (type 1 and type 2 diabetes) may be associated to diminished lung function and, in particular, decreased vital capacity, and the association between chronic obstructive pulmonary disease (COPD) and type 2 diabetes may be due to a shared inflammatory process. Also, the alteration in circulating endothelial progenitor cells found in respiratory disease, the metabolic syndrome and cardiovascular disease reflect a common condition of endothelial dysfunction.

Differential effects of hyperinsulinemia and hyperaminoacidemia on leucine-carbon metabolism in vivo. Evidence for distinct mechanisms in regulation of net amino acid deposition.

The effects of physiologic hyperinsulinemia and hyperaminoacidemia, alone or in combination, on leucine kinetics in vivo were studied in postabsorptive healthy subjects with primed-constant infusions of L-[4,5-3H]leucine and [1-14C]alpha-ketoisocaproate (KIC) under euglycemic conditions. Hyperinsulinemia (approximately 100 microU/ml) decreased (P less than 0.05 vs. baseline) steady state Leucine + KIC rates of appearance (Ra) from proteolysis, KIC (approximately leucine-carbon) oxidation, and nonoxidized leucine-carbon flux (leucine----protein). Hyperaminoacidemia (plasma leucine, 210 mumol/liter), with either basal hormone replacement or combined to hyperinsulinemia, resulted in comparable increases in leucine + KIC Ra, KIC oxidation, and leucine----protein (P less than 0.05 vs. baseline). However, endogenous leucine + KIC Ra was suppressed only with the combined infusion. Therefore, on the basis of leucine kinetic data, hyperinsulinemia and hyperaminoacidemia stimulated net protein anabolism in vivo by different mechanisms. Hyperinsulinemia decreased proteolysis but did not stimulate leucine----protein. Hyperaminoacidemia per se stimulated leucine----protein but did not suppress endogenous proteolysis. When combined, they had a cumulative effect on net leucine deposition into body protein.

Intracellular lactate- and pyruvate-interconversion rates are increased in muscle tissue of non-insulin-dependent diabetic individuals.

The contribution of muscle tissues of non-insulin-dependent diabetes mellitus (NIDDM) patients to blood lactate appearance remains undefined. To gain insight on intracellular pyruvate/lactate metabolism, the postabsorptive forearm metabolism of glucose, lactate, FFA, and ketone bodies (KB) was assessed in seven obese non-insulin-dependent diabetic patients (BMI = 28.0 +/- 0.5 kg/m2) and seven control individuals (BMI = 24.8 +/- 0.5 kg/m2) by using arteriovenous balance across forearm tissues along with continuous infusion of [3-13C1]-lactate and indirect calorimetry. Fasting plasma concentrations of glucose (10.0 +/- 0.3 vs. 4.7 +/- 0.2 mmol/liter), insulin (68 +/- 5 vs. 43 +/- 6 pmol/liter), FFA (0.57 +/- 0.02 vs. 0.51 +/- 0.02 mmol/liter), and blood levels of lactate (1.05 +/- 0.04 vs. 0.60 +/- 0.06 mmol/liter), and KB (0.48 +/- 0.04 vs. 0.29 +/- 0.02 mmol/liter) were higher in NIDDM patients (P < 0.01). Forearm glucose uptake was similar in the two groups (10.3 +/- 1.4 vs. 9.6 +/ 1.1 micromol/min/liter of forearm tissue), while KB uptake was twice as much in NIDDM patients as compared to control subjects. Lactate balance was only slightly increased in NIDDM patients (5.6 +/- 1.4 vs. 3.3 +/- 1.0 micromol/min/liter; P = NS). A two-compartment model of lactate and pyruvate kinetics in the forearm tissue was used to dissect out the rates of lactate to pyruvate and pyruvate to lactate interconversions. In spite of minor differences in the lactate balance, a fourfold increase in both lactate- (44.8 +/- 9.0 vs. 12.6 +/- 4.6 micromol/min/liter) and pyruvate-(50.4 +/- 9.8 vs. 16.0 +/- 5.0 micromol/min/liter) interconversion rates (both P < 0.01) were found. Whole body lactate turnover, assessed by using the classic isotope dilution principle, was higher in NIDDM individuals (46 +/- 9 vs. 21 +/- 3 micromol/min/kg; P < 0.01). Insights into the physiological meaning of this parameter were obtained by using a whole body noncompartmental model of lactate/pyruvate kinetics which provides a lower and upper bound for total lactate and pyruvate turnover (NIDDM = 46 +/- 9 vs. 108 +/- 31; controls = 21 +/- 3 - 50 +/-13 micromol/min/kg). In conclusion, in the postabsorptive state, despite a trivial lactate release by muscle, lactate- and pyruvate-interconversion rates are greatly enhanced in NIDDM patients, possibly due to concomitant impairment in the oxidative pathway of glucose metabolism. This finding strongly suggest a major disturbance in intracellular lactate/pyruvate metabolism in NIDDM.

Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism.

To determine whether a resistance to insulin in type 1, insulin-dependent diabetes mellitus (IDDM) is extended to both glucose and amino acid metabolism, six normal subjects and five patients with IDDM, maintained in euglycemia with intravenous insulin administration, were infused with L-[4,5-3H]leucine (Leu) and [1-14C]alpha ketoisocaproate (KIC). Steady-state rates of leucine-carbon appearance derived from protein breakdown (Leu + KIC Ra) and KIC (approximately leucine) oxidation were determined at basal and during sequential euglycemic, hyperinsulinemic (approximately 40, approximately 90 and approximately 1,300 microU/ml) clamps. In the euglycemic postabsorptive diabetic patients, despite basal hyperinsulinemia (24 +/- 6 microU/ml vs. 9 +/- 1 microU/ml in normals, P less than 0.05), Leu + KIC Ra (2.90 +/- 0.18 mumol/kg X min), and KIC oxidation (0.22 +/- 0.03 mumol/kg X min) were similar to normal values (Leu + KIC Ra = 2.74 +/- 0.25 mumol/kg X min) (oxidation = 0.20 +/- 0.02 mumol/kg X min). During stepwise hyperinsulinemia, Leu + KIC Ra in normals decreased to 2.08 +/- 0.19, to 2.00 +/- 0.17, and to 1.81 +/- 0.16 mumol/kg X min, but only to 2.77 +/- 0.16, to 2.63 +/- 0.16, and to 2.39 +/- 0.08 mumol/kg X min in the diabetic patients (P less than 0.05 or less vs. normals at each clamp step). KIC oxidation decreased in normal subjects to a larger extent than in the diabetic subjects. Glucose disposal was reduced at all insulin levels in the patients. In summary, in IDDM: (a) Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations. (b) At euglycemic hyperinsulinemic clamps, lower glucose disposal rates and a defective suppression of leucine-carbon appearance and oxidation were observed. We conclude that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present.

Educating diabetic patients about insulin use: changes over time in certainty and correctness of knowledge.

AIM: Diabetic patients should understand their disease correctly and be sure of what they know, but certainty is rarely considered by educators. Furthermore little is known about how certainty changes with time after an educational intervention. To clarify this, in 38 patients with type 1 diabetes (0.3-36 years duration) we analysed the effect of a course on insulin use by administering a questionnaire before the course, after the course and 1 and 3 years later. METHODS: Answers, accompanied by a subjective estimate of the degree of certainty, were assigned to mastered knowledge (certainty>or=90%, correctness>or=90%), hazardous knowledge (certainty>or=90%, correctnessor=90%) and residual knowledge (total-[mastered+hazardous+uncertain]). Answers were then counted and changes in distribution among areas were analysed by the chi2 test. We also followed the fate of wrong answers. RESULTS: The course increased mastered knowledge, while other types of knowledge decreased. With time mastered knowledge decreased, patients losing both correctness and certainty. The loss affected declarative knowledge, based purely on theory, more than procedural knowledge, which concerns the way things are done. Wrong answers, mostly given with high degree of certainty, were heterogeneous since some became correct after the course, some remained wrong, some became wrong after the course, some became mistaken after having been corrected earlier. CONCLUSIONS: The analysis of certainty helps in evaluating patient's knowledge; programmes tending to improve procedural knowledge are more likely to have long lasting effects; wrong answers need to be considered on a individual basis.

Regulation of postprandial whole-body proteolysis in insulin-deprived IDDM.

Suppression of tissue proteolysis is an important mechanism of postprandial protein anabolism, and it may be mediated by insulin, hyperaminoacidemia, or both. To evaluate whether insulin is essential in the regulation of this process, we have investigated the effect of mixed-meal ingestion on whole-body protein breakdown in insulin-deprived insulin-dependent diabetes mellitus (IDDM) patients and normal control subjects. Endogenous phenylalanine and leucine rate of appearance (Ra) from proteolysis were measured at steady-state conditions using a multiple stable isotope technique before and after the constant administration of a synthetic mixed meal. In the postabsorptive state, the IDDM patients exhibited accelerated intracellular leucine Ra (IDDM, 2.64 +/- 0.19 mumol.min-1.kg-1; control, 2.02 +/- 0.08 mumol.min-1.kg-1; P < 0.05) and plasma phenylalanine Ra (IDDM, 0.73 +/- 0.03 mumol.min-1.kg-1; control, 0.61 +/- 0.04 mumol.min-1.kg-1; P < 0.05). During meal ingestion, endogenous phenylalanine and leucine Ra values were suppressed in both the insulin-deficient IDDM (P < 0.05) and control subjects (P < 0.05). Although postmeal endogenous leucine and phenylalanine Ra values remained greater (P < 0.05) in IDDM, the delta changes from the basal endogenous leucine Ra (IDDM, -0.56 +/- 0.11 mumol.min-1.kg-1; control, -0.56 +/- 0.09 mumol.min-1.kg-1) and phenylalanine Ra (IDDM, -0.13 +/- 0.01 mumol.min-1.kg-1; control, -0.14 +/- 0.02 mumol.min-1.kg-1) were similar in both groups. In the IDDM patients, the postmeal increases from the basal leucine concentration were onefold greater (P < 0.05) than in the control-subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression and stimulation mechanisms controlling glucagon secretion in a case of islet-cell tumor producing glucagon, insulin, and gastrin.

The mechanisms controlling secretion of glucagon and other pancreatic hormones were studied in a patient affected with multihormone-secreting islet-cell tumor. Fasting glucagon levels (3,000 pg./ml.) rose to 10 ng./ml. following arginine stimulation. While oral glucose load and intravenous glucose infusion did not suppress glucagon secretion, insulin administration induced a prompt depression in glucagon levels. Glucagon, insulin, and gastrin levels were suppressed by somatostatin while calcium infusion caused a paradoxical increase. It is suggested that only some of the stimulation-inhibition mechanisms were conserved in this case of glucagon-secreting pancreatic tumor.

Effect of ethanol, acetaldehyde, and acetate on insulin and glucagon secretion in the perfused rat pancreas.

The effects of varying concentrations of ethanol (1, 10, and 30 mM) and its metabolites (1 mM acetate and 1 and 10 mM acetaldehyde) on insulin and glucagon secretion induced by glucose (11.1 mM) and arginine (20 mM) were studied in isolated perfused pancreas of Sprague-Dawley rats. Ethanol and its metabolites did not significantly modify basal secretion of the two hormones. Ethanol reduced glucose-induced insulin secretion by means of a dose-related effect. Arginine-induced insulin output did not seem to be influenced to any significant degree. Acetate and acetaldehyde significantly inhibited glucose and arginine-induced insulin secretion. While ethanol (10 and 30 mM ) did not modify glucagon output during arginine perfusion, acetate and acetaldehyde markedly enhanced it. The block of insulin secretion and the increased secretion of glucagon could explain the diabetogenic effect of ethanol demonstrated in vivo. The mechanism by which ethanol acts on the pancreatic beta- and alpha-cells is discussed.

Ketone body metabolism in NIDDM. Effect of sulfonylurea treatment.

We assessed the metabolism of the two KBs, AcAc and 3-BOH; the relationships between ketogenesis and FFA inflow rate; and the effect of chronic sulfonylurea treatment in mild NIDDM patients (plasma glucose less than 10 mM). We studied 10 nonobese NIDDM patients in a crossover, randomized, double-blind, placebo-controlled fashion. Each patient was studied 4 times: after a run-in period with placebo, after 3 mo of placebo treatment, after 3 mo of glibenclamide treatments, respectively, and after 3 mo of sulfonylurea treatment during an acute exogenous Intralipid infusion. Ten normal, nondiabetic subjects served as the control group. Glibenclamide treatment decreased plasma FFAs. When these substrates were exogenously increased, plasma FFAs were comparable with placebo and baseline concentrations. In NIDDM patients, baseline and placebo blood total KB concentration was significantly higher than in control subjects (216 +/- 22 and 244 +/- 25, respectively vs. 127 +/- 18 microM; P less than 0.01). Glibenclamide treatment significantly decreased total KBs to 177 +/- 19 microM (P less than 0.05). When FFAs were exogenously increased, total KBs were similar to the placebo and baseline period. In the baseline study, the AcAc/3-BOH ratio was 0.72 +/- 0.06 in control subjects, whereas in NIDDM patients, the ratio was 1.61 +/- 0.13 at baseline (P less than 0.001 vs. control subjects), 1.66 +/- 0.15 during placebo, 1.57 +/- 0.09 during glibenclamide (NS vs. baseline), and 1.51 +/- 0.23 during glibenclamide plus placebo FFAs. Both the AcAc interconversion rate to 3-BOH and the 3-BOH interconversion rate to AcAc were significantly lower in NIDDM patients than in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients.

Endothelium-dependent and -independent vascular responses were assessed in 10 NIDDM patients and 6 normal subjects with no evidence of atherosclerotic disease. Changes in forearm blood flow and arteriovenous (AV) serum nitrite/nitrate (NO2-/NO3-) concentrations were measured in response to intra-arterial infusion of acetylcholine (ACh) (7.5, 15, 30 microg/min, endothelium-dependent response) and sodium nitroprusside (SNP) (0.3, 3, 10 microg/min, endothelium-independent response). Insulin sensitivity (determined by minimal model intravenous glucose tolerance test) was lower in NIDDM patients (0.82 +/- 0.20 vs. 2.97 +/- 0.29 10(4) min x microU(-1) x ml(-1); P < 0.01). Baseline forearm blood flow (4.8 +/- 0.3 vs. 4.4 +/- 0.3 ml x 100 ml(-1) tissue x min(-1); NS), mean blood pressure (100 +/- 4 vs. 92 +/- 4 mmHg; NS), and vascular resistance (21 +/- 1 vs. 21 +/- 1 units; NS), as well as their increments during ACh and SNP, infusion were similar in both groups. No difference existed in baseline NO2-/NO3- concentrations (4.09 +/- 0.33 [NIDDM patients] vs. 5.00 +/- 0.48 micromol/l [control subjects]; NS), their forearm net balance (0.31 +/- 0.08 [NIDDM patients] vs. 0.26 +/- 0.08 micromol/l x 100 ml(-1) tissue x min(-1); NS), and baseline forearm glucose uptake. During ACh infusion, both NO2- and NO3- concentrations and net balance significantly increased in both groups, whereas glucose uptake increased only in control subjects. When data from NIDDM and control groups were pooled together, a correlation was found between the forearm AV NO2- and NO3- differences and blood flow (r = 0.494, P = 0.024). On the contrary, no correlation was evident between NO2- and NO3- concentrations or net balance and insulin sensitivity. In summary, 1) no difference existed in basal and ACh-stimulated NO generation and endothelium-dependent relaxation between uncomplicated NIDDM patients and control subjects; 2) in both NIDDM and control groups, forearm NO2- and NO3- net balance following ACh stimulation was related to changes in the forearm blood flow; and 3) ACh-induced increase in forearm blood flow was associated with an increase in glucose uptake only in control subjects but not in NIDDM patients. In conclusion, our results argue against a role of impaired NO generation and blood flow regulation in determining the insulin resistance of uncomplicated NIDDM patients; rather, it supports an independent insulin regulation of hemodynamic and metabolic effects.

The hemodynamic abnormalities in short-term insulin deficiency: the role of prostaglandin inhibition.

It has been suggested that the hemodynamic derangements present in diabetic ketoacidosis are the results not only of profound volume depletion but also of the effects of increased production of vasodilating prostaglandins (PGs), principally PGI2, released by adipose tissue. In animal and in vitro models, prostaglandin synthesis is increased during insulin deficiency. We assessed the effects of short-term ketosis on the metabolic and hemodynamic variables of 10 IDDM patients free from long-term complications and of 9 normal control subjects after a 7-day randomized double-blind indomethacin (INDO) (50 mg q.i.d.) or placebo treatment period. Calf blood flow (CBF), postocclusive reactive hyperemia (PORH), and recovery half-time (an index of overall perfusion) after PORH were measured by plethysmography. Left ventricular and myocardial functions were also studied in each different condition during placebo and INDO treatment in IDDM patients. During placebo treatment, the increase in CBF during ketosis was higher (1.75 +/- 0.29 ml / min / 100 ml muscle) than during INDO (0.85 +/- 0.17 ml / min) / 100 ml muscle; P = 0.007). PORH was similar in baseline conditions, during ketosis, and in recovery in both the placebo and INDO arms. Recovery half-time significantly increased during placebo (10 +/- 2; 200%; P < 0.01) but not during INDO (1 +/- 1; 106%; NS) treatment. In normal control subjects, insulin deficiency did not induce any significant effect on hemodynamic variables. In IDDM patients, during placebo treatment, ketosis increased both the cardiac index (from 3.4 +/- 0.7 to 4.1 +/- 0.81 / min / m; P < 0.01) and the stroke index (from 42 +/- 8 to 49 +/- 7 ml/m2; P < 0.01) without changes in left ventricular ejection fraction but with a significant increase in both left and right ventricular end-diastolic volumes. Metabolic recovery induced a normalization of these parameters. INDO treatment significantly blunted these alterations. In summary, we showed that during acute insulin deficiency, INDO-sensitive mechanisms mediate vascular disturbances. Moreover, INDO treatment was capable of completely preventing the cardiac venous return and the left ventricular alterations. INDO does not interfere with the overall ketogenetic process or with insulin-induced metabolic recovery.

Hyperglucagonemia stimulates phenylalanine oxidation in humans.

Glucagon stimulates in vitro liver phenylalanine (Phe) degradation, thus inducing net protein catabolism. Whether these effects occur also in vivo in humans is not known. Therefore, we studied the effects of physiological hyperglucagonemia on Phe rate of appearance (Ra), hydroxylation, and oxidation in seven normal volunteers during infusions of somatostatin with replacement doses of insulin and growth hormone. Steady-state Phe kinetics were evaluated using the L-[1-14C]Phe tracer both at the end of a 3-h basal glucagon replacement period (glucagon concentration: 212 +/- 115 ng/l) and after a 3-h hormone infusion at the rate of approximately 3 ng x kg-1 x min-1 (--> 654 +/- 280 ng/l). Hyperglucagonemia did not change plasma Phe concentration and Ra but increased Phe oxidation by approximately 30% (P < 0.01). Oxidation was also increased by approximately 24% (P < 0.01) using plasma [14C]tyrosine (Tyr) specific activity as a precursor pool. Phe hydroxylation to Tyr estimated by assuming a fixed ratio of Tyr to Phe Ra (0.73) did not change. Nonhydroxylated Phe disposal decreased by approximately 6% (P = 0.08). These data show that in humans in the postabsorptive state, hyperglucagonemia, with near maintenance of basal insulin and growth hormone concentrations, stimulates Phe oxidation but not Phe hydroxylation, suggesting a different regulation of these two Phe catabolic steps. Glucagon may also reduce Phe availability for protein synthesis.

Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria.

We assessed blood pressure (BP), body weight, renal hemodynamics, and insulin sensitivity (by euglycemic-hyperinsulinemic clamp) in nine normoalbuminuric and seven microalbuminuric IDDM patients after 6 days on a low-sodium diet (20 mEq) and after 6 days on a high-sodium diet (250 mEq). In microalbuminuric but not in normoalbuminuric IDDM patients, switching from a low to a high-sodium diet was associated with a significant increase in mean BP (from 92 +/- 3 to 101 +/- 4 mmHg; P < 0.001) and in body weight (2.91 +/- 0.63 vs. 1.47 +/- 0.26 kg; P < 0.05). Moreover, under high-sodium conditions, angiotensin II infusion (3 ng x kg(-1) x min(-1)) caused a greater increase in mean BP (14 +/- 2 vs. 7.4 +/- 1 mmHg; P < 0.05) and a smaller reduction in renal plasma flow (-122 +/- 29 vs. -274 +/- 41 ml x min(-1) x 1.73 m2; P < 0.05) in microalbuminuric than in normoalbuminuric IDDM patients. Under low sodium conditions, aldosterone increments after angiotensin II infusion were lower (P < 0.05) in microalbuminuric than in normoalbuminuric IDDM patients. Insulin-mediated glucose disposal was not affected by sodium dietary content, but it was lower in microalbuminuric (P < 0.05) than in normoalbuminuric IDDM patients. The salt-induced changes in mean BP were related to insulin sensitivity (r = -0.78; P < 0.001). In conclusion, in IDDM patients, microalbuminuria is associated with 1) an increased responsiveness of BP to salt intake and angiotensin II, 2) impaired modulation of renal blood flow, and 3) insulin resistance. Therefore, salt sensitivity in IDDM patients clusters with other factors that are likely to play an important role in the pathogenesis of diabetic nephropathy and its cardiovascular complications.

Insulin sensitivity, binding, and kinetics in pancreatogenic and type I diabetes.

Pancreatogenic diabetes (PD), secondary either to chronic calcific pancreatitis or to pancreatectomy, is characterized by higher frequency of hypoglycemic events during insulin therapy in comparison with type I insulin-dependent diabetes (IDD). Not only glucagon deficiency, but an enhanced peripheral tissue sensitivity to insulin could account for this metabolic behavior. We investigated several facets of insulin action, e.g., tissue sensitivity to insulin, insulin binding to red cells, and insulin kinetics in seven patients with PD in comparison with type I. Tissue sensitivity to insulin was evaluated by means of the glucose-insulin clamp technique as M/I x 100 ratio (mg . kg .-1 min-1/muU . ml-1), where M is the amount of glucose infused by Biostator GCIIS to clamp BG at basal level and I is the free insulin plateau concentration achieved by a primed-constant insulin infusion. At high BG 15 h after the last injection of regular insulin M/I x 100 was 7.79 (range 4.25-9.75) in PD and 4.20 (range 1.20-6.91) in D (P less than 0.05). At low and equal BG M/I x 100 was 8.55 (range 6.35-9.72) in PD and 3.42 (range 1.19-6.75) in D (P less than 0.01). The rate of endogenous glucose production was nearly totally suppressed in both groups of patients. Just before the two clamps, 125I-insulin specific binding to red cells was studied. The maximum specific binding was significantly higher in PD than in D at high BG (10.7 +/- 1.7 vs. 7.4 +/- 0.8/10(9) red cells) and at low and equal BG (12.4 +/- 1.2 vs. 6.8 +/- 0.8). Receptor concentration also was significantly higher in PD thant in D (P less than 0.02) while no significant differences were found in high affinity (Ke). Insulin kinetic data were analysed by using both "Model independent" (or noncompartmental) method and compartmental modeling. Patients with PD had significantly higher (P less than 0.05) plasma clearance of insulin.