Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy.

The limited success achieved in controlling diabetes and its complications with conventional insulin therapy suggests the need for reevaluation of the appropriateness of insulin administration protocols. Indeed, conventional subcutaneous insulin administration produces slowly changing blood insulin levels and suboptimal hepatocyte insulinization resulting in impaired hepatic capacity for processing incoming dietary glucose. The novel approach to insulin administration known as chronic intermittent intravenous insulin therapy (CIIIT) delivers insulin in a pulsatile fashion and achieves physiological insulin concentration in the portal vein. Done as a weekly outpatient procedure combined with daily intensive subcutaneous insulin therapy, this procedure has been shown to (1) significantly improve glycemic control while decreasing the incidence of hypoglycemic events, (2) improve hypertension control, (3) slow the progression of overt diabetic nephropathy, and (4) reverse some manifestations of diabetic autonomic neuropathy (e.g., abnormal circadian blood pressure pattern, severe postural hypotension, and hypoglycemia unawareness).

Effect of intensive insulin therapy on progression of overt nephropathy in patients with type 1 diabetes mellitus.

OBJECTIVE: To assess the effects of chronic (long-term) intermittent intravenous insulin therapy (CIIIT) on the progression of overt nephropathy in patients with type 1 diabetes mellitus. METHODS: We undertook a retrospective longitudinal three-center study of 31 patients with type 1 diabetes mellitus and overt nephropathy, who were receiving intensive subcutaneous insulin therapy (four insulin injections daily) and weekly CIIIT. All study patients had follow-up consultations weekly for at least 12 months (mean duration, 37.0 +/- 4.6 months). Each patient had monthly hemoglobin A(1c) (by high-performance liquid chromatography) and semiannual creatinine clearance determinations. RESULTS: The hemoglobin A(1c) levels declined significantly from 8.6 +/- 0.6% to 7.6 +/- 0.3% (P = 0.0062) during the study period. The creatinine clearance remained essentially unchanged (from 46.1 +/- 3.0 mL/min per 1.73 m 2 at baseline to 46.0 +/- 3.9 mL/min per 1.73 m 2 at the end of the observation period, with an average annualized slope increase of 3.39 +/- 1.5 mL/min per year--no significant difference). CONCLUSION: The addition of CIIIT to intensive subcutaneous insulin therapy in patients with type 1 diabetes mellitus seems to arrest or appreciably reduce the progression of overt diabetic nephropathy, as well as substantially improve their glycemic control.

Effect of intensive insulin therapy on abnormal circadian blood pressure pattern in patients with type I diabetes mellitus.

OBJECTIVE: To assess the effect of tight glycemic control on the abnormal circadian BP pattern associated with IDDM. DESIGN: Retrospective, randomized control trial. SETTING: Diabetes Research Institute, ambulatory. PATIENTS: Seventy-four IDDM patients (22M/52F) on intensive subcutaneous insulin therapy (ISIT) were selected for this study. INTERVENTIONS: Group A patients (11M/25F) underwent, in addition to ISIT, weekly chronic intermittent intravenous insulin therapy (CIIIT) (TT Aoki et al, Lancet, 1993, 432:515-8). Group B patients (11M/27F) were continued on ISIT alone. All study patients were followed for 3 months on this regimen. They were seen weekly by the investigators and underwent monthly HbA1c determinations and 24-h ambulatory BP monitoring. RESULTS: Glycemic control improved significantly in group A subjects (HbA1c decreased from 7.9% to 7.2%, p = 0.0002) but changed little in the group B subjects (p = NS). The night/day systolic BP ratio decreased from 0.97 to 0.94 (-3.10%) in group A and increased from 0.95 to 0.98 (+3.16%) in group B subjects (p = 0.224). The night/day diastolic ratio decreased from 0.93 to 0.90 (-3.23%) in group A and increased from 0.91 to 0.94 (+3.29%) in group B subjects (p = 0.0037). CONCLUSIONS: CIIIT performed in IDDM patients on ISIT further improves their glycemic control and tends to reverse or at least prevent further deterioration of their abnormal circadian BP pattern.

Effect of chronic intermittent intravenous insulin therapy on antihypertensive medication requirements in IDDM subjects with hypertension and nephropathy.

OBJECTIVE: The prevalence of systemic hypertension is increased in patients with diabetes. In this prospective, randomized, crossover clinical trial, we assessed antihypertensive effects of chronic intermittent intravenous insulin therapy (CIIIT) on insulin-dependent diabetes mellitus (IDDM) subjects with hypertension and nephropathy by monitoring the amount of antihypertensive medication (AHM) required to maintain blood pressure (BP) < or = 140/90 mmHg. RESEARCH DESIGN AND METHODS: After a stabilization period, 26 hypertensive IDDM subjects were randomly assigned to a control or treatment phase for 3 months and then crossed over into the opposite phase for another 3 months. Addition of CIIIT during the treatment phase was the only procedural difference between the control and treatment phases. RESULTS: The AHM dosage requirements for maintenance of the baseline BP levels decreased significantly (46%; P < 0.0001) and linearly over time (P < 0.0058) during the treatment phase, while remaining essentially unchanged during the control phase. CONCLUSIONS: Our data suggest that CIIIT markedly improves BP control, as evidenced by the significantly reduced AHM dosage requirements in subjects with IDDM and hypertension, possibly through an improvement in vascular reactivity.

Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus.

An important defect in insulin-dependent diabetes mellitus (IDDM) is that the liver does not meet its full fuel-processing function, because many of the enzymes involved depend on high insulin concentrations in the portal vein. We tried to reactivate the liver by long-term treatment of IDDM patients with intravenous insulin in pulses, with the aim of achieving high portal-vein concentrations during and after a glucose meal. We studied 20 IDDM patients with brittle disease; despite use of a four-injection regimen with manipulation of insulin doses, diet, and physical activity, and frequent clinic visits for at least a year, these patients still had wide swings in blood glucose and frequent hypoglycaemic reactions. The intermittent therapy consisted of 7-10 pulses of intravenous insulin, infused while the patient was ingesting carbohydrate, primarily glucose, during the first hour of a 3 h treatment; three treatments were given in a day. After 2 consecutive days' treatment, patients were treated for 1 day per week. No patient was withdrawn from the study. At the time of this analysis the duration of intermittent treatment ranged from 7 to 71 months (mean 41 [SE 5] months). Haemoglobin A1C concentrations declined from 8.5 (0.4)% at the end of the stabilisation phase to 7.0 (0.2)% at the analysis point (p = 0.0003). During the same time the frequencies of major and minor hypoglycaemic events also fell significantly (major 3.0 [1.1] to 0.1 [0], minor 13.0 [2.6] to 2.4 [0.8] per month; both p < 0.0001). Because the use of saline rather than insulin pulses would have led to unacceptable hyperglycaemia we opted for a historical control design. The absence of a true control group limits the interpretation of these preliminary results, but we believe further studies of hepatic and muscle metabolism before and after long-term intermittent intravenous insulin therapy would be worth while.

The heated dorsal hand vein: an alternative arterial sampling site.

Studies of substrate flux, isotope activity and metabolic balance frequently require arterial sampling. We evaluated: (1) whether substrate concentrations obtained from heated dorsal hand veins (HDHV) were comparable to samples obtained from the radial artery, (2) whether heat sufficient to arterialize HDHV altered contralateral forearm blood flow thus affecting flux calculations, (3) whether a +14 heating pad equaled a cumbersome +700 heating chamber, and (4) whether HDHV showed a dose-response curve to varying heat loads. In 12 normals, dorsal hand temperature was raised from 31.8 +/- 0.6 degrees C to 39.8 +/- 0.8 degrees C (chamber) and 39.3 +/- 0.3 degrees C (pad). Basal contralateral forearm blood flow (3.37 +/- 0.7 ml/100 ml tissue/min) was not significantly altered in the chamber (3.39 +/- 0.5 ml) or the pad (3.44 +/- 0.5 ml). Skin temperature of the unheated hand, an index of superficial blood flow (31.5 +/- 0.7 degrees C) did not change significantly in the chamber (31.6 +/- 0.7 degrees C) or the pad (31.2 +/- 0.7 degrees C). Forearm blood flow did not change with heating in eight postoperative patients. Comparative arterial and HDHV blood gases and 10 metabolic substrates from simultaneously drawn samples at various temperatures showed HDHV PO2 approached but did not equal arterial PO2 at temperatures greater than 39 degrees C. Glucose, amino acid, and substrate concentrations were comparable at 39 degrees C and did not change with increasing temperature. HDHV can reliably determine arterial substrate concentrations using an inexpensive heating pad. In cool environments (20-22 degrees C), contralateral forearm blood flow is not significantly altered. There is no benefit to heating the hand above 39 degrees C.

Studies of alloxan toxicity on the beta cell.

The ability of sugars to protect the beta cell from alloxan diabetes is highly stereospecific. The alpha anomer, which is present in equilibrium in both glucose and 3-O-methyl glucose (3-OMG) at approximately 34 per cent, provides greater protection than the beta anomer. The greater protection of the alpha anomer of glucose is present fifteen seconds between its administration and alloxan, but there is no difference in protection following a thirty-second interval. The nonmetabolized analogue, 3-OMG, provides even greater protection than glucose, and this higher affinity is expressed both by the lower dose necessary to provide protection, as well as by the higher dose of mannoheptulose needed to remove thr protection. Mannoheptulose not only removes the protection provided by exogenous glucose but sensitizes the beta cell to the toxic effects of alloxan in the fasting state, probably by inhibiting the protection provided by endogenous glucose. Mannoheptulose is able to remove glucose protection before, with, or after the administration of glucose prior to alloxan injection. Finally, the protective effect of both glucose and 3-OMG is time-related, and the protection not only is due to absolute concentration but also appears to be affected by a changing concentration.