The effect of continuous subcutaneous insulin infusion on cardiac performance during exercise in insulin-dependent diabetics

To assess the effects of improved glycaemic control on the right and left ventricular ejection fraction (RVEF and LVEF), we performed radionuclide angiocardiography at rest and during exercise in nine insulin-dependent diabetics with a diabetes duration between 2 and 35 years (mean 12 years) and in 10 control subjects. The diabetics were investigated before and after 7 days' treatment with continuous subcutaneous insulin infusion (CSII). The diabetics had a significantly smaller rise in exercise-induced LVEF during normoglycaemia than in the hyperglycaemic state. In contrast to the control subjects, the diabetics, independent of glycaemic control, did not increase the end-diastolic volume and did not decrease the end-systolic volume during exercise. Our data indicate a preclinical abnormal left ventricular function in young diabetics without long-term diabetic complications. The dysfunction seems unrelated to changes in the loading of the heart and appears to be caused by decreased contractile reserve of the myocardium.     

Effects of continuous subcutaneous insulin infusion versus multiple injections on insulin receptors in insulin-dependent diabetics

We compared continuous subcutaneous insulin infusion (CSII) versus multiple injections (MI) in the treatment of insulin-dependent diabetes mellitus (IDDM) to assess the effect of glucose control on monocyte insulin receptors. Each IDDM patient (n = 8) was treated for 2 mo by MI (HS Ultralente and AC boluses of regular insulin) and for 2 mo by CSII in a randomized fashion. Prestudy preprandial/postprandial blood glucose levels were 199 +/- 33/261 +/- 28 mg/dl and improved to 124 +/- 12/156 +/- 13 mg/dl during MI and to 115 +/- 11/151 +/- 11 mg/dl during CSII. Glycosylated hemoglobin before the study was 10.1 +/- 0.5% and decreased to 8.8 +/- 0.4 and 8.3 +/- 0.3% during MI and CSII, respectively. The specific 125I-labeled insulin binding to circulating monocytes in a group of nonobese controls (n = 17) was 4.6 +/- 0.2%. In our poorly controlled diabetics during conventional therapy, the 125I-insulin binding was decreased to 3.7 +/- 0.3 (P less than .025). This was not significantly affected by MI despite good glucose control (4.0 +/- 0.3%). With CSII, however, good glucose control was associated with normalization of 125I-insulin binding to monocytes (4.7 +/- 0.27%). The affinity of the insulin receptors was normal before the study and was not affected by either MI or CSII. In conclusion, these observations demonstrate that in IDDM, intensive therapy by MI and CSII resulted in similar good glucose control, but only CSII resulted in normalization of insulin receptors on circulating monocytes.     

Diurnal pattern of insulin requirements in insulin-dependent diabetics

A total of 35 experiments in which insulin-dependent diabetics were connected to an artificial beta cell (Biostator) for feedback control of blood glucose during at least 24 h, were evaluated. Only 14 experiments, however, were available for analysis, since interruptions of more than 45 min/24 h in feedback control due to clots in analyser tubing occurred in those remaining. In these 14 experiments the 24-h insulin-infusion pattern was analysed. Basal insulin requirements (BIR), (between 01.00 and 04.00 hours) was found to be 0.178 +/- 0.044 (SD) mU/kg X min. Insulin requirements increased in the early morning (04.00-07.00 hours) to 0.231 +/- 0.084 mU/kg X min (P less than 0.01). A significant correlation between BIR and 24-h insulin requirement was found (r = 0.53, P less than 0.05). Insulin requirements per kJ following breakfast were higher than after lunch, 0.57 +/- 0.20 muU/kg X min X kJ versus 0.41 +/- 0.29 muU/kg X min X kJ (P less than 0.05).     

Early morning glycaemia and the metabolic consequences of delaying breakfast/morning insulin. A comparison of continuous subcutaneous insulin infusion and multiple injection therapy with human isophane or human ultralente insulin at bedtime in insulin-dependent diabetics

We studied morning glycaemia and metabolic consequences of delaying morning insulin/breakfast in insulin-dependent diabetics on (i) continuous subcutaneous insulin infusion (CSII) (n = 27), (ii) multiple-injection therapy (MI) with human isophane insulin at bedtime (MI/human isophane) (n = 23) and (iii) MI with human ultralente insulin at bedtime (MI/human ultralente) (n = 14). After an overnight fast, food and insulin (except for the basal infusion on CSII) were withheld, and blood glucose, serum free insulin and serum betahydroxybutyrate were followed from 0800 hours to 1300 hours. At all times blood glucose was lowest on CSII, intermediate on MI/human isophane and highest on MI/human ultralente; serum free insulin was highest on CSII, intermediate on MI/human ultralente and lowest on MI/human isophane; serum betahydroxybutyrate was lowest on CSII, intermediate on MI/human ultralente and highest on MI/human isophane. Blood glucose rose significantly on MI/human isophane (p less than 0.001) and CSII (p less than 0.02); serum free insulin declined significantly on MI/human isophane (p less than 0.001), and betahydroxybutyrate rose significantly on all regimens. Morning metabolic control is better with CSII than MI. Human isophane insulin is preferable to human ultralente insulin overnight in MI. Delaying morning insulin is not advisable on intensified insulin regimens, being most unfavourable with MI/human isophane.     

HLA-antigens and immunity to insulin in insulin-dependent diabetics with or without diabetic neuropathy

In order to define genetic, immunological and metabolic risk factors and markers associated with diabetic neuropathy (DN) 47 insulin-dependent diabetic patients with neuropathy were compared to 30 age-matched insulin-dependent diabetes mellitus (IDDM) patients without neuropathy. Patients with diabetic neuropathy more often had proliferative retinopathy and Albustix positive proteinuria than patients without neuropathy. Judged by haemoglobin A1 (HbA1) concentrations measured during the preceding two years glycaemic control was worse in patients with than without diabetic neuropathy. The frequency of HLA-antigens DR3, DR4, DR3/DR4, B8, and B15 were increased and those of DR2 and B7 decreased in the diabetic patients. The frequency of any of these HLA-antigens did not differ in patients with or without diabetic neuropathy. There were no significant differences in the frequencies of insulin antibodies or proliferative responses to insulin antigens between patients with or without diabetic neuropathy. However, patients who were HLA-DR3/DR4 heterozygotes and had diabetic neuropathy responded to insulin antigens more often by proliferation than DR3/DR4 positive patients without diabetic neuropathy. Thus poor glycaemic control is associated with an increased risk for diabetic neuropathy. Patients with DR3/DR4 heterozygocity and failing to respond to insulin antigens by proliferation seem to be less prone to develop diabetic neuropathy.     

Catheter infections in insulin-dependent diabetics on continuous ambulatory peritoneal dialysis.

We compared a group of 60 insulin-dependent diabetics maintained on CAPD with 60 nondiabetic matched controls to determine if the diabetic patients were at increased risk for catheter-related infections. Although catheter infection rates were 17% higher in the diabetics (1.4/year versus 1.2/year in nondiabetics), time to first catheter infection was not different between the groups (p = 0.6). Rates of peritonitis, peritonitis associated with catheter infection, multiple catheter infection, and catheter removal were also similar among the diabetics and controls. S. aureus caused 52% (42/81) of the catheter infections in the diabetics and 60% (35/58) in the controls. More catheter infections in the nondiabetics versus the diabetics lacked drainage or resulted in sterile cultures (17/75 versus 7/88 respectively, p less than or equal to 0.01), but the significance of this finding is uncertain. In conclusion, we did not find insulin-dependent diabetes mellitus to be a statistically significant risk factor for catheter-related infections.     

Effects of exercise on the absorption of insulin glargine in patients with type 1 diabetes

OBJECTIVE: To study the effects of exercise on the absorption of the basal long-acting insulin analog insulin glargine (Lantus), administered subcutaneously in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 13 patients (12 men, 1 woman) with type 1 diabetes on a basal-bolus insulin regimen were studied. (125)I-labeled insulin glargine at the usual basal insulin dose was injected subcutaneously into the thigh on the evening (2100) before the study day on two occasions 1 week apart. Patients were randomly assigned to 30 min intense exercise (65% peak oxygen uptake [Vo(2peak)]) on one of these visits. The decay of radioactive insulin glargine was compared on the two occasions using a thallium-activated Nal gamma counter. Blood samples were collected at regular intervals on the study days to assess plasma glucose and insulin profiles. RESULTS: No significant difference was found in the (125)I-labeled insulin glargine decay rate on the two occasions (exercise vs. no exercise; repeated-measures ANOVA, P = 0.548). As expected, a significant fall in plasma glucose was observed over the exercise period (area under curve above fasting [DeltaAUC] glucose: -0.39 +/- 0.11 vs. -1.30 +/- 0.16 mmol . l(-1) . h(-1); nonexercise vs. exercise; P = 0.001), but insulin levels did not differ significantly on the two occasions (DeltaAUC insulin: -2.1 +/- 3.9 vs. 1.5 +/- 6.2 pmol . l(-1) . h(-1); nonexercise versus exercise; P = 0.507). CONCLUSIONS: An intense 30-min period of exercise does not increase the absorption rate of the subcutaneously injected basal long-acting insulin analog insulin glargine in patients with type 1 diabetes.     

Relationship between the urinary excretion of albumin and retinol-binding protein in insulin-dependent diabetics

The glomerular and proximal tubular function of the diabetic kidney was investigated. The urinary excretion (relative clearance) of albumin, a marker of glomerular function, and retinol binding protein (RBP), a low molecular weight (LMW) protein and marker of proximal tubular function, was determined in insulin-dependent diabetics. No correlation between the relative clearances of albumin and RBP was observed. LMW proteinuria without microalbuminuria was observed in 27 patients which suggests that tubular dysfunction may be an early stage in the development of diabetic nephropathy. Microalbuminuria was found in 16 patients while a mixed type of proteinuria (microalbuminuria and LMW proteinuria) was present in 56 patients several of whom had advanced nephropathy with elevated serum levels of RBP and creatinine. It is suggested that a combination of tubular and glomerular malfunction may be responsible for some cases of mixed proteinuria.     

Comparison of the biologic activity of porcine and semisynthetic human insulins using the glucose-controlled insulin infusion system in insulin-dependent diabetes

Semisynthetic human insulin is prepared from porcine pancreas by chemical methods involving the substitution of porcine B-30 alanine with threonine. To compare the effectiveness of porcine and semisynthetic human insulins, eight insulin-dependent diabetic patients were evaluated during two separate periods using a glucose-controlled insulin infusion system. During each 36-h period, patients received either porcine or semisynthetic human insulin. Patients ingested mixed meals. The mean daily insulin requirements for porcine and semisynthetic human insulins were 84 +/- 9 U and 85 +/- 6 U (+/- SEM), respectively (P = NS). Mean blood glucose values were similar at 95 +/- 1 mg/dl for porcine and 101 +/- 3 mg/dl with semisynthetic human insulin (P = NS). Prior metabolic control or insulin antibody levels did not correlate with intravenous insulin requirements. These studies indicate that semisynthetic human insulin is as effective as porcine insulin in maintaining near-normal blood glucose control in short-term intravenous studies using artificial pancreas techniques in insulin-dependent diabetes.     

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

OBJECTIVE: To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. RESEARCH DESIGN AND METHODS: Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. RESULTS: The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and 68.9 +/- 3.5 from 2.5 h onward; and hexameric insulin 20.7 +/- 1.9 from 0 to 2 h, 45.6 +/- 5.0 from 2.5 to 5 h, and 70.6 +/- 6.3 from 5 h onward. CONCLUSIONS: Association state is a major determinant of rates of absorption of insulin and insulin analogues. The lag phase and the subsequent increasing rate of subcutaneous soluble insulin absorption can be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process.     

Synergistic interaction between exercise and insulin on peripheral glucose uptake.

The interaction of exercise and insulin on glucose metabolism was examined in 10 healthy volunteers. Four study protocols were used: study 1: plasma insulin was raised by approximately 100 microunits/ml while plasma glucose was maintained at basal levels for 2 h (insulin clamp). Study 2: subjects performed 30 min of bicycle exercise at 40% of VO2 max. Study 3: an insulin clamp was performed as per study 1. Following 60 min of sustained hyperinsulinemia, however, subjects exercised for 30 min as per study 2. Study 4: subjects were studied as per study 3 except that catheters were inserted into the femoral artery and vein to quantitate leg glucose uptake. During the 60-90 min period of hyperinsulinemia (study 1), glucose uptake averaged 8.73 +/- 0.10 mg/kg per min. With exercise alone (study 2), the increment in peripheral glucose uptake was 1.43 +/- 0.30 mg/kg per min. When hyperinsulinemia and exercise were combined (study 3), glucose uptake averaged 15.06 +/- 0.98 mg/kg per min (P less than 0.01) and this was significantly (P less than 0.001) greater than the sum of glucose uptake when exercise and the insulin clamp were performed separately. The magnitude of rise in glucose uptake correlated closely with the increase in leg blood flow (r = 0.935, P less than 0.001), suggesting that the synergism is the result of increased blood flow and increased capillary surface area to exercising muscle. More than 85% of total body glucose metabolism during studies 1 and 3 was accounted for by skeletal muscle uptake. These results demonstrate that (a) insulin and exercise act synergistically to enhance glucose disposal in man, and (b) muscle is the primary tissue responsible for the increase in glucose metabolism following hyperinsulinemia and exercise.     

Effects of brief physical exercise on the concentrations of immunoreactive superoxide dismutase isoenzymes in human plasma.

Effects of cycle ergometer exercise (approximately 75% VO2max for 15 min) on the concentrations of immunoreactive Mn- and CuZn-superoxide dismutases (SOD) in plasma were studied on 10 male students. During the experimental period, Mn-SOD concentration did not vary substantially. On the other hand, CuZn-SOD concentration decreased markedly at 15 min and 24 hr after the exercise; that is, CuZn-SOD appeared to differ virtually from Mn-SOD in recovery pattern.     

Effect of muscular exercise on plasma C-peptide and insulin in obese non-diabetics and diabetics,Type II

Summary. The levels of plasma insulin and C-peptide during exercise and subsequent recovery have been determined in obese non-diabetics, obese diabetics Type II and middle-aged female controls. It has been found that exercise reduces levels of peptides both in the control and in the obese non-diabetic group. This effect of acute exercise was found blunted in the obese diabetic group. Non-diabetic obese subjects pretreated with phentolamine showed no reduction either in plasma insulin or C-peptide levels during exercise. During the recovery, the level of plasma insulin returned promptly to the pre-exercise value in the control group but increased above the resting value in obese subjects, both non-diabetic and diabetic. In controls and non-diabetic obeses the increment of C-peptide: insulin molar ratio occurred early after the onset of exercise and then returned to the resting value despite the exercise being continued. The plasma C-peptide:insulin molar ratios were reduced during the first 15 min of recovery period in obese non-diabetic subjects and returned to normal in the next 15 min. The latter may suggest that reduced insulin removal could also contribute to the increase in plasma insulin values in the obeses during recovery.     

Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise

Nine insulin-dependent diabetics and six healthy controls were studied at rest, during, and after 60 min of bicycle exercise at a work load corresponding to 45% of their maximal oxygen intake. The catheter technique was employed to determine splanchnic and leg exchange of metabolites. FFA turnover and regional exchange was evaluated using [14C]oleate infusion. Basal glucose (13.8 +/- 1.1 mmol/l), ketone body (1.12 +/- 0.12 mmol/l), and FFA (967 +/- 110 mumol/l) concentrations were elevated in the diabetics in comparison with controls. In the resting state, splanchnic ketone acid production in the diabetics was 6-10-fold greater than in controls. Uptake of oleic acid by the splanchnic bed was increased 2-3-fold, and the proportion of splanchnic FFA uptake converted to ketones (61%) was threefold greater than in controls. In contrast, splanchnic fractional extraction of oleic acid was identical in diabetics and controls. A direct relationship was observed between splanchnic uptake and splanchnic inflow (plasma concentration X hepatic plasma flow) of oleic acid that could be described by the same regression line in the diabetic and control groups. During exercise, splanchnic ketone production rose in both groups. In the control group the increase in ketogenesis was associated with a rise in splanchnic inflow and in uptake of oleic acid, a rise in splanchnic fractional extraction of oleate, and an increase in the proportion of splanchnic FFA uptake converted to ketone acids from 20-40%. In the diabetic group, the increase in ketogenesis occurred in the absence of a rise in splanchnic inflow or uptake of oleic acid, but was associated with an increase in splanchnic fractional extraction of oleic acid and a marked increase in hepatic conversion of FFA to ketones, so that the entire uptake of FFA was accountable as ketone acid output. Splanchnic uptake of oleic acid correlated directly with splanchnic oleic acid inflow in both groups, but the slope of the regression line was steeper than in the resting state. Plasma glucagon levels were higher in the diabetic group at rest and during exercise, while plasma norepinephrine showed a twofold greater increment in response to exercise in the diabetic group (to 1,400-1,500 pg/ml). A net uptake of ketone acids by the leg was observed during exercise but could account for less than 5% of leg oxidative metabolism in the diabetics and less than 1% in controls. Despite the increase in ketogenesis during exercise, a rise in arterial ketone acid levels was not observed in the diabetics until postexercise recovery, during which sustained increments to values of 1.8-1.9 mmol/l and sustained increases in splanchnic ketone production were observed at 30-60 min. The largest increment in blood ketone acids and in splanchnic ketone production above values observed in controls thus occurred in the diabetics after 60 min of recovery from exercise. We concluded that: (a) In the resting state, increased ketogenesis in the diabetic is a consequence of augmented splanchnic inflow of FFA and increased intrahepatic conversion of FFA to ketones, but does not depend on augmented fractional extraction of circulating FFA by the splanchnic bed. (b) Exercise-induced increases in ketogenesis in normal subjects are due to augmented splanchnic inflow and fractional extraction of FFA as well as increased intrahepatic conversion of FFA to ketones. (c) When exercise and diabetes are combined, ketogenesis increases further despite the absence of a rise in splanchnic inflow of FFA. An increase in splanchnic fractional extraction of FFA and a marked increase intrahepatic conversion of FFA to ketones accounts for the exaggerated ketogenic response to exercise in the diabetic. (d) Elevated levels of plasma glucagon and/or norepinephrine may account for the increased hepatic ketogenic response to exercise in the diabetic. (e) Ketone utilization by muscle increases during exercise but constitutes a quantitatively minor oxidative fuel for muscle even in the diabetic. (f) The accelerated ketogenesis during exercise in the diabetic continues unabated during the recovery period, resulting in an exaggerated postexercise ketosis.     

Serum and urine N-acetyl-beta-D-glucosaminidase in diabetics on diagnosis and subsequent treatment, and stable insulin dependent diabetics.

N-Acetyl-beta-D-glucosaminidase (NAG) activity has been measured in the serum and urine of diabetics. Results have shown significantly higher levels of serum NAG in newly diagnosed diabetics (945 +/- 372 units/ml) compared to non-diabetic controll (668 +/- 225, p less than 0.005) and the levels were reduced by treatment (778 +/- 218, p less than 0.05). Changes occurred in the same direction when urinary NAG was measured falling from a mean of 572 +/- 298 units/mg urinary creatinine, on diagnosis to 291 +/- 176 after treatment (p less than 0.005), as compared with 177 +/- 86 in non-diabetic controls. Established insulin-treated diabetics had a urinary NAG activity of 461 +/- 440 and a serum NAG activity of 790 +/- 245. No correlation was found between urine NAG activity and urine glucose (r = 0.315), or serum NAG and serum glucose (r = 0.273). An assessment of this enzyme is made in relation to early microangiopathy.