Stimulation of glucose uptake in skeletal muscle using bolus or continuous insulin delivery.

We investigated glucose uptake in the non-cyclically perfused rat hindlimb in response to continuous infusion (CI) or bolus injection (BI) of insulin. Ten mM glucose was infused at 3 ml/min, venous glucose was monitored at two minute intervals, and glucose uptake was calculated on the basis of arteriovenous-difference and expressed as micron/min/100 g body wt. Insulin BI given every ten minutes equaled the amount of insulin given by CI for ten minutes. Insulin doses of 1500, 3000, 6000, and 45,000 microU/30 min showed no significant difference between the two modes of delivery in either onset of stimulation or maximal stimulation of glucose uptake. At the lowest insulin dose tested (1500 microU/30 min) neither BI nor CI stimulated glucose uptake above the control of 1.849 micron/min/100 g. A dose response curve for glucose uptake was obtained using insulin boluses ranging from 2000 to 20,000 microU. Insulin uptake by the muscle was always greater when insulin was administered CI. Net disappearance of immunoreactive insulin over the entire 30 minutes of perfusion was 29.4 +/- 2.6% for CI but only 7.1 +/- 1.6% for BI. Thus in the perfused rat hindlimb, stimulation of glucose uptake in skeletal muscle is comparable with BI and CI delivery of insulin but insulin uptake by the muscle is several-fold greater with CI delivery.

Deep neck infection complicated by diabetes mellitus. Report of a case.

A poorly controlled diabetic patient who developed a life-threatening deep neck infection from a periodontal abscess is presented. Despite treatment reflecting the current surgical and medical approach to management of this infection, he failed to show the consistent improvement that would be expected in a nondiabetic patient. The physiologic differences in the defense systems of the diabetic versus the nondiabetic host are discussed, and general guidelines for identification of the diabetic patient are offered.

Effect of sulfonylurea therapy and plasma glucose levels on hemoglobin A1c in type II diabetes mellitus.

It is well known that hemoglobin A1c reflects plasma glucose concentrations in patients with diabetes mellitus. To examine hemoglobin A1c and plasma glucose relationships in sulfonylurea-treated patients, 25 patients with well-controlled type II diabetes (fasting plasma glucose 128 +/- 6 mg/dl, hemoglobin A1c 7.6 +/- 0.5 percent) were evaluated in a double-blind study. This study was divided into two phases (periods I and II). During period I each patient was given a diet plus a placebo and was followed every two weeks until the mean of two consecutive plasma glucose determinations was more than 50 mg/dl above the initial plasma glucose concentration obtained while the patient was taking sulfonylurea. At that point each patient was switched in a double-blind fashion to either diet plus a placebo or diet plus tolazamide. Fasting plasma glucose concentrations increased to 178 +/- 9 mg/dl (p less than 0.005) for all patients by week 2 of period I. The increase in hemoglobin A1c concentration was seen to lag behind the increasing fasting plasma glucose concentration by four to six weeks. Fasting plasma glucose and hemoglobin A1c concentrations returned to values indistinguishable from initial values in patients who were given tolazamide and who responded to it. A positive correlation was noted when the hemoglobin A1c concentration was compared with the fasting plasma glucose concentration measured four to six weeks previously.

Prolonged effect of insulin on glucose uptake by rat skeletal muscle.

The fate of insulin, as it relates to its action on skeletal-muscle glucose uptake, was studied in non-cyclically perfused rat hindlimbs. Insulin (1m-i.u./ml) with and without (125)I-labelled insulin was infused intra-arterially for 5 or 6min. Net glucose uptake and the release of (125)I-labelled insulin into the venous effluent were evaluated by arteriovenous-difference measurements for an additional 24-32min. The infusion of insulin for 5min promoted glucose uptake, an effect that persisted throughout a subsequent 25min of perfusion in the absence of insulin. The addition of insulin antibody to the perfusate in the presence of insulin blocked the action of insulin on glucose uptake, but it failed to alter insulin action if the muscle tissue had been exposed to insulin before addition of antibody. When (125)I-labelled albumin was infused for 6min, venous effluent radioactivity decayed rapidly and remained HClO(4)-insoluble and there was no significant tissue retension of radioactivity. Comparable experiments in which (125)I-labelled insulin was infused for 6min revealed that the venous effluent radioactivity decayed more slowly, a significant amount of the (125)I-labelled insulin appeared as fragments (HClO(4)-soluble) and there was a significant retention of radioactivity in the tissue. Radioactivity in muscle tissue biopsies obtained 28min after infusion of (125)I-labelled insulin was associated largely with intact insulin and a peptide of mol.wt. 2400. The total radioactivity retained in the muscle at this time was 7% of the amount infused. An insulin bolus (1i.u.) failed to increase the discharge of this tissue-associated radioactivity. These results suggest that insulin and a product of insulin metabolism persists in muscle tissue long after the arterial presence of insulin ends. This tissue residence and processing of insulin may be important components of insulin's prolonged action on glucose uptake by skeletal muscle.

Glucose delivery: a modulator of glucose uptake in contracting skeletal muscle.

To evaluate glucose delivery and neuromuscular activity as modulators of glucose uptake in skeletal muscle, rat hindlimbs from pentobarbital-anesthetized rats were perfused in the presence of electrically stimulated muscular contractions. Glucose delivery was varied by altering non-cyclic perfusate flow. When flow was increased from 3 to 12 ml/min glucose disappearance increased from 1.1 +/- 0.2 to 4.0 +/- 0.2 mumol/min per 100 g rat (P less than 0.001). When glucose delivery was held constant, glucose disappearance was unaltered during muscular contractions. Insulin enhanced glucose disappearance, and its effect was unaltered during muscular contractions. Muscular contractions increased oxygen disappearance by two- to 3.5-fold and lactate appearance by 4.5- to fivefold (P less than 0.02). It was concluded that glucose delivery and insulin modulate glucose disappearance in isolated perfused rat hindlimbs. Electrical stimulation of muscle enhances lactate appearance and oxygen disappearance but does not alter glucose disappearance when flow is held constant. Because blood flow to muscle increases during exercise in vivo, increased glucose delivery may be a modulator of the augmented muscle glucose consumption observed under these conditions.

Peripheral diabetic neuropathy treated with amitriptyline and fluphenazine.

The pain of diabetic peripheral neuropathy responds poorly to current modes of treatment. We treated eight patients with this disorder whose pain was refractory to standard regimens but who experienced remarkable pain relief within two to five days after treatment with fluphenazine hydrochloride, amitriptyline hydrochloride, or a combination of the two. In four patients whose regimens were discontinued, pain recurred within two days and again remitted on reinstitution of the drug regimens. These findings suggest that fluphenazine alone or in combination with amitriptyline may be of benefit in treating the painful peripheral neuropathy associated with diabetes.

Clinical evaluation of somatostatin as a potential ajunct to insulin in the management of diabetes mellitus.

To determine whether somatostatin, an inhibitor of glucagon and growth hormone secretion, might be useful as an adjunct to insulin the management of diabetic hyperglycaemia, seven insulin-requiring diabetic men were given somatostatin (100 microgram/h, IV) continuously for 3 days after their diabetes had been treated intensively by diet and insulin on a metabolic ward. During infusion of somatostatin and despite reduction in average insulin dose exceeding 50%, there was improvement in diabetic control as assessed by postprandial hyperglycaemia, 24-h glycosuria and the average daily serum glucose level and its fluctuation; when somatostatin was discontinued, but insulin doses held constant, diabetic control rapidly worsened. No adverse effects were observed. These results indicate that somatostatin plus insulin can be a more effective regimen than insulin alone in controlling diabetic hyperglycaemia. A longer acting and more selective somatostatin preparation may prove useful as an adjunct to insulin in the management of diabetes.

Insulin-glucose dynamics during flow-through perfusion of the isolated rat hindlimb.

The dose-response relationship between glucose and insulin concentration and utilization in skeletal muscle was examined in hindlimbs of overnight fasted normal male rats. The perfusion was by flow-through technique utilizing an artificial perfusate containing beef erythrocytes. Glucose disappearance correlated significantly with insulin concentration. Insulin effect was detected within 5 minutes. When arterial glucose was 10 mM, glucose disappearance during maximal insulin stimulation was fivefold greater than glucose disappearance in the absence of insulin. A half-maximal effect occurred at an insulin concentration of 411 U per ml. Arteriovenous difference of immunoreactive insulin during a single passage thorugh the hindlimb averaged 16.7% over the range of 50 to 10,000 U per ml. In the presence or absence of insulin, glucose disappearance was positively correlated with glucose concentration up to a glucose concentration range of 30 to 45 mM. In this range and above glucose uptake averaged twelvefold above that observed for 5 mM glucose. When insulin (500 muU/ml) was added at any glucose concentration, glucose disappearance was augmented. The data thus indicate that rat skeletal muscle is a major site of insulin metabolism. In addition to the effect of insulin on glucose uptake by the muscle cell, glucose mass action appears to be quantitatively equipotent.