Comparison of Metabolic Deterioration between Insulin Analog and Regular Insulin after a 5-Hour Interruption of a Continuous Subcutaneous Insulin Infusion in Type 1 Diabetic Patients1

An interruption of continuous sc insulin infusion (CSII) of the insulin analog lispro should result in a more rapid metabolic deterioration of type 1 diabetic patients because of its pharmacokinetic characteristics. We analyzed the metabolic changes occurring during a 5-h interruption of CSII and the 5 h after restarting the pump in 10 type 1 diabetic patients. The study was a randomized, cross-over, open label design comparing insulin analog [Lispro (LP)] and regular insulin [Velosuline (VE)]. Plasma glucose, free insulin, glucagon,β -hydroxybutyrate (β-OHB), and nonesterified fatty acids (NEFA) were measured every hour from 0700 h (time zero) to 1700 h (600 min). After stopping CSII, the plasma glucose level was significantly higher in the LP group than in the VE group (P < 0.05–0.01). The plasma free insulin level decreased significantly with the two treatments, but was significantly lower with LP than with VE (P < 0.05–0.01). Plasma NEFA increased more rapidly and was significantly higher in the LP group than in the VE group (P < 0.01–0.05). Plasma β-OHB increased earlier with LP, but was not statistically different between the treatments. After restarting the pump, plasma glucose decreased with LP, but continued to increase with VE, and the plasma free insulin peak occurred earlier and was greater with LP than with VE (P < 0.05). Plasma NEFA and β-OHB levels decreased significantly with the two treatments, but more dramatically with LP treatment. Thus, a short interruption of Lispro in CSII is associated with an earlier, greater metabolic deterioration, but Lispro corrected this metabolic deterioration more effectively.

Effects of insulin and amino acid infusion on leucine and phenylalanine kinetics in type 1 diabetes

To evaluate the anabolic effects of hyperinsulinemia and hyperaminoacidemia on amino acid (and protein) metabolism in type 1 (insulin-dependent) diabetes mellitus (IDDM), we studied leucine and phenylalanine kinetics in nine IDDM and seven control subjects, both at basal euglycemic conditions and during a euglycemic hyperinsulinemic clamp (approximately 60-80 microU/ml of plasma free insulin), combined with an intravenous infusion of amino acids (AA), which doubled plasma concentrations of most AA. In the basal state, euglycemia was maintained in IDDM subjects at the expense of a peripheral free insulin level (16 +/- 2 microU/ml) greater (P less than 0.05) than controls (9 +/- 1 microU/ml). Despite that, leucine rate of appearance (Ra), alpha-ketoisocaproate oxidation (approximating leucine-carbon oxidation), and nonoxidative leucine disposal, were greater (P less than 0.05) in IDDM than in control subjects. Phenylalanine Ra was slightly but not significantly greater in IDDM vs. control subjects. During the clamp, at comparable plasma free insulin and amino acid concentrations, oxidation was similar in the two groups, endogenous leucine and phenylalanine Ra remained significantly greater (P less than 0.05) in IDDM than in normal subjects, and leucine disposal tended also to be greater in IDDM subjects. Thus, in IDDM subjects maintained at euglycemia, endogenous Ra of essential amino acid(s) (index of endogenous proteolysis) is increased, both in the postabsorptive state and after hyperinsulinemia combined with hyperaminoacidemia, while leucine utilization for protein synthesis is not impaired.

Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM

Increased gluconeogenesis contributes to fasting hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). We examined whether insulin inhibits gluconeogenesis from lactate by altering the fate of lactate and/or by reducing lactate flux. Seven patients with NIDDM (age 51 +/- 4 yr, body mass index 28 +/- 2 kg/m2) were studied before and 3 wk after achieving normoglycemia with evening insulin therapy. Basal glucose production (Ra) and utilization were measured overnight [( 3-3H]glucose infusion from 9 P.M. to 8 A.M.) and lactate turnover and conversion to glucose between 4 and 8 A.M. [( U-14C]lactate infusion) before and after insulin therapy. During insulin therapy, fasting plasma glucose decreased from 188 +/- 13 to 99 +/- 7 mg/dl (P less than 0.001) due to inhibition of glucose Ra from 3.0 +/- 0.1 to 2.2 +/- 0.1 mumol.kg-1.min-1 (P less than 0.005). Plasma free insulin increased from 6 +/- 1 to 11 +/- 1 microU/ml (P less than 0.005). Plasma lactate concentrations (1.1 +/- 0.2 vs. 1.0 +/- 0.1 mmol/l before vs. after insulin therapy) and the lactate turnover rate (15.6 +/- 0.9 vs. 14.2 +/- 0.8 mumol.kg.min) remained unchanged, whereas the amount of glucose formed from lactate decreased from 2.0 +/- 0.1 to 1.4 +/- 0.2 mumol.kg-1.min-1 (P less than 0.02) and the percent of lactate turnover converted to glucose decreased from 26 +/- 1 to 20 +/- 2% (P less than 0.05). We conclude that insulin inhibits overnight glucose Ra from lactate by decreasing the proportion of lactate diverted towards gluconeogenesis rather than by altering lactate availability or total flux.

Somatostatin reduces posthypoglycemic insulin resistance in insulin-dependent diabetes mellitus

In order to study whether somatostatin reduces posthypoglycemic insulin resistance, hypoglycemia was induced between 7.00 and 8.00 h by an iv infusion of insulin with and without somatostatin (250 μg/h) in 6 male patients with insulin-dependent diabetes mellitus (IDDM). Exogenous glucagon was infused to substitute for the suppression of its endogenous release (1.0-1.5 ng·kg−1·min−1). Insulin resistance was assessed by a somatostatin-insulin-infusion test (SIGIT) between 11.00 and 15.00 h. In the study without hypoglycemia, blood glucose was kept close to 6 mmol/l from 8.00 h until start of the SIGIT. In both hypoglycemic studies similar nadir blood glucose levels were achieved and hypoglycemia evoked the same increase of plasma epinephrine and cortisol, whereas plasma glucagon remained at its basal level. The growth hormone response to hypoglycemia was suppressed by somatostatin. At the onset of the SIGIT, the plasma levels of the counterregulatory hormones had returned to basal, and blood glucose and plasma free insulin concentrations were almost identical. During the SIGIT there were no differences in plasma free insulin or counterregulatory hormone levels. Insulin resistance, as seen following hypoglycemia, was not demonstrable in the study with somatostatin. It is concluded that somatostatin reduces insulin resistance following hypoglycemia in patients with IDDM. It is therefore suggested that an analogue with a specific GH release inhibiting property may be useful in reducing glycemic instability when given as adjunct therapy to insulin in patients with labile glycemic control.

Comparison of insulin regimens in the therapy of type 1 diabetes

The major problems with one or two daily subcutaneous injections of fast and intermediate acting insulins are morning hyperglycaemia and nocturnal hypoglycaemia. These problems can be avoided to a great extent by giving a third injection at bedtime. However, the kinetics of plasma free insulin during these insulin regimens is unphysiological and appropriate meal related plasma insulin peaks cannot be achieved. The new intensified methods of insulin delivery, multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) are more physiological. Consequently, a near normal glycaemic control can be achieved with these regimens; more often with CSII than with MDI. The risk of complications of CSII is on the other hand slightly greater. The importance and need of intensified insulin therapy in the treatment of insulin dependent diabetes is not yet fully settled. At the present it is not a primary form of treatment and indicated only if the conservative insulin regimens fail.

The importance of plasma free insulin and counterregulatory hormones for the recovery of blood glucose following hypoglycaemia in Type 1 diabetics

After induction of hypoglycaemia in 31 Type 1 (insulin-dependent) patients, the 10 patients with the slowest recovery of blood glucose from hypoglycaemia were arbitrarily compared with the 10 patients with the fastest recovery of blood glucose. No differences were found between the two groups regarding response of glucagon to hypoglycaemia, whereas the epinephrine (2-fold), norepinephrine (2.4-fold) and cortisol responses were significantly greater in the group with the slow recovery. The plasma free insulin concentrations were higher (2-fold) in the group with slow recovery from 30 min after stop of insulin and throughout the study. This may be explained by a 3-fold greater amount of insulin binding antibodies in this group compared to the group with fast recovery from hypoglycaemia. An inverse significant correlation was demonstrated between the rates of recovery and the amounts of insulin binding antibodies in all the patients (P < 0.02). This implicates that enhanced counterregulatory hormone responses in the group with the slow recovery from hypoglycaemia could not compensate for the hypoglycaemic effect of a concomitant higher plasma free insulin concentration. Insulin binding antibodies, acting as a depot of circulating insulin, may be a risk factor of prolonged hypoglycaemia in Type 1 diabetics.