Diabetes control and complications.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive treatment of patients with insulin-dependent diabetes mellitus (IDDM) can substantially reduce the onset and progression of diabetic retinopathy, nephropathy, and neuropathy. The major risk associated with intensive treatment is recurrent hypoglycemia. Implementation of intensive treatment recommendations is difficult but should be considered and probably recommended to most patients with IDDM. If intensive treatment is impractical, any improvement in glycemic control is probably beneficial. Improved glycemic control should be recommended to most patients with non-insulin-dependent diabetes mellitus (NIDDM). The use of insulin in patients with NIDDM is controversial, especially in patients who are overweight, overeating, and minimally symptomatic.

Near normalization of metabolism of IDDM: comparison of continuous subcutaneous (CSII) versus intraperitoneal (CIPII) insulin delivery.

The effects of continuous insulin infusion given subcutaneously (CSII) and intraperitoneally (CIPII) on 24 h "metabolic" profile of four insulin dependent diabetic volunteers were assessed. When the insulin dose delivered is adjusted to achieve a near match of the peripheral plasma glucose profile, the 24 h profiles of free fatty acids, glycerol, lactate and beta-hydroxybutyrate and the hormones, insulin, glucagon, cortisol and catecholamines were identical. These results suggest that CIPII has no advantage over CSII in normalizing of the metabolism of the insulin dependent diabetic.

Exercise in insulin-dependent diabetes mellitus: the effect of continuous insulin infusion using the subcutaneous, intravenous, and intraperitoneal sites.

The metabolic response to exercise in insulin-dependent diabetic (IDD) man was assessed during continuous insulin infusion using the subcutaneous (CSII), intravenous (CIVII), and intraperitoneal (CIPII) routes. During the basal period, plasma glucose levels were higher with CIPII (153 +/- 17 mg/dl) than with CSII (117 +/- 13 mg/dl) or CIVII (118 +/- 17 mg/dl). Basal free insulin concentrations were similar for CSII (12.3 +/- 10 microU/ml) and CIVII (12.4 +/- 1.4 MicroU/ml) but lower in CIPII (8.5 +/- 1.0 microU/ml, P less than 0.05). Exercise on a stationary bicycle at 75 W for 60 min produced a decline of plasma glucose in each protocol that was significantly only during CIVII (55 +/- 11 mg/dl, P less than 0.01). Insulin levels remained unchanged throughout the study period in all protocols. In normals, insulin values decreased during exercise and remained below basal levels through the recovery period (P less than 0.05), while plasma glucose remained unchanged. Plasma glucagon and epinephrine levels were similar in all protocols and remained unchanged with exercise, while plasma norepinephrine tended to be higher than normal in all diabetic subjects. Significant differences between normal and diabetic subjects (P less than 0.05) were observed for blood ketone bodies, while blood lactate, glycerol, and plasma FFA were similar. Normalization of intermediary metabolites occurred only with CIVII. Continuous insulin infusion provides near-normal glycemic and metabolic control before, during and following exercise in IDD man. However, to produce normal blood concentrations of intermediary metabolites during exercise, the insulin infusion rate may be excessive in terms of its hypoglycemic effect. CSII appears to be a safe, accessible, and adequate method for treating diabetic man during exercise.

Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dichloroacetate.

Dichloroacetate is known to reduce plasma cholesterol and triglyceride in patients with Fredrickson Types IIb or IV hyperlipoproteinemia. We now report the effects of chronic, oral dichloroacetate administration (as the sodium salt) in two patients with severe homozygous familial hypercholesterolemia. Dichloroacetate markedly reduced serum total and low density lipoprotein cholesterol levels and lowered the low density lipoprotein to high density lipoprotein cholesterol ratio. One patient developed a polyneuropathy while receiving dichloroacetate which resolved following discontinuation of the drug. Because of its apparent toxicity, dichloroacetate cannot be recommended for chronic oral use. Investigation of the mechanism of its lipid-lowering effect, however, may provide insight into the pathogenesis and treatment of hypercholesterolemic disorders.

Carbon tetrachloride toxicity potentiated by isopropyl alcohol. Investigation of an industrial outbreak.

Fourteen workers in an isopropyl alcohol packaging plant became ill after accidental exposure to carbon tetrachloride. In four, renal failure or hepatitis developed. Isopropyl alcohol potentiation of carbon tetrachloride toxicity has been shown previously only in rats. Acetone, a product of isopropyl alcohol metabolism, is a major potentiator of carbon tetrachloride toxicity. Workers had elevated levels of acetone in samples of expired alveolar gas and thus were metabolically predisposed to carbon tetrachloride injury. Stricter limits for industrial carbon tetrachloride exposure should be established where concomitant isopropyl alcohol use occurs.

Time course of termination of the glucose transport action of insulin in adipocytes.

Rapid sequence measures of changes in the rate of 14CO2 production from [14C]glucose bathing the cells was abruptly reduced from 20 to 4 microunits/ml. Interpretation of the data in terms of glucose transport was based on calibration experiments that described the time course of change in 14CO2 production when [14C]glucose entry into adipocytes was slowed by reducing the specific activity of [14C]glucose in the incubation medium. All experiments were performed at 37 degrees in Krebs-Ringer bicarbonate buffer at pH 7.4. Termination of the glucose transport action of insulin (which includes insulin-receptor disassociation and all other steps leading to decelerated glucose entry) began within 2 min and was complete within 30 min. The transition from one steady state rate of glucose transport to the other could be approximated by an exponential process occurring with a half-time of 14 min. For comparison, the time course of initiation of the glucose transport action of insulin was measured under the same conditions. The transition curve was virtually identical.

Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men.

The effect of glucagon (50 ng/kg/min) on arterial glycerol concentration and net splanchnic production of total ketones and glucose was studied after an overnight fast in four normal and five insulin-dependent diabetic men. Brachial artery and hepatic vein catheters were inserted and splanchnic blood flow determined using indocyanine green. The glucagon infusion resulted in a mean circulating plasma level of 4,420 pg/ml. In the normal subjects, the glucagon infusion resulted in stimulation of insulin secretion indicated by rising levels of immunoreactive insulin and C-peptide immunoreactivity. Arterial glycerol concentration (an index of lipolysis) declined markedly and net splanchnic total ketone production was virtually abolished. In contrast, the diabetic subjects secreted no insulin (no rise in C-peptide immunoreactivity) in response to glucagon. Arterial glycerol and net splanchnic total ketone production in these subjects rose significantly (P=<0.05) when compared with the results in four diabetics who received a saline infusion after undergoing the same catheterization procedure.Net splanchnic glucose production rose markedly during glucagon stimulation in the normals and diabetics despite the marked rise in insulin in the normals. Thus, the same level of circulating insulin which markedly suppressed lipolysis and ketogenesis in the normals failed to inhibit the glucagon-mediated increase in net splanchnic glucose production. It is concluded (a) that glucagon at high concentration is capable of stimulating lipolysis and ketogenesis in insulin-deficient diabetic man; (b) that insulin, mole for mole, has more antilipolytic activity in man than glucagon has lipolytic activity; and (c) that glucagon, on a molar basis, has greater stimulatory activity than insulin has inhibitory activity on hepatic glucose release.

Effect of glucagon on net splanchnic cyclic AMP production in normal and diabetic men.

Glucagon activates hepatic adenylate cyclase, thereby increasing acutely the liver content of cyclic AMP (cAMP) as well as the release of cAMP into the hepatic vein. Insulin, on the other hand, antagonizes this glucagon-mediated cAMP production, thus providing a hypothetical mechanism through which insulin might correct some of the metabolic abnormalities of diabetes. To study this hormonal interaction in man, net splanchnic cAMP production (NScAMPP) was investigated in normal and insulin-dependent diabetic men under basal conditions and in response to intravenous glucagon, 50 ng/kg/min for 2 h. In normals (n=19), basal hepatic vein cAMP concentration was 23.6+/-1.1 nM and NScAMPP was 1.7+/-0.6 nmol/min. Glucagon stimulated NScAMPP in four normal subjects to a peak of 99.6+/-43 nmol/min at 25 min with a subsequent fall to 12.4+/-5.1 nmol/min by 90 min despite continuing glucagon infusion. Endogenous insulin secretion was stimulated as indicated by rising levels of immunoreactive insulin and C-peptide (connecting peptide) immunoreactivity, raising the possibility that endogenous insulin might be responsible for the fall in NScAMPP that followed the initial spike. In the diabetics (n=8), basal hepatic vein cAMP concentration was 24.7+/-1.2 nM and NScAMPP was undetectable. Glucagon stimulated NScAMPP in five diabetics to a peak of 169.9+/-42.6 with a subsequent fall to 17.4+/-3.9 nmol/min by 90 min even though endogenous insulin secretion was not stimulated (no rise in C-peptide immunoreactivity). Although the mean increase in NScAMPP was greater in the diabetics, the two groups did not differ significantly.Conclusions. In normal resting man the liver is a significant source of circulating cAMP. Diabetics do not release abnormally large amounts of hepatic cAMP under basal conditions. Glucagon markedly enhances hepatic cAMP release with a spike-decline pattern in both normal and diabetic men. The decline in hepatic cAMP release despite continuing glucagon stimulation is due to factors other than a stimulation of insulin secretion.