Eaton Rp

Insulin Suppresses Its Own Secretion In Vivo

This study addressed the controversial question of whether a negative—insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 ± 1.4 mU/min during the control study to 4.0 ± 1.2 and 3.2 ± 0.9 mU/min during plasma insulin levels of 34 ± 4 and 61 ± 6 μU/ml, respectively (P < .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

Normalization of Plasma Insulin Profiles with Intraperitoneal Insulin Infusion in Diabetic Man

SummaryThis study examined the feasibility of normalizing the plasma insulin profile in five insulin deficient diabetic males. Acute meal-related increases in plasma free insulin concentration were achieved by administering short-acting insulin intraperitoneally with a pre-programmed portable rotary splenoid driven pump. This insulin response was compared to that achieved when short-acting insulin was injected subcutaneously 15 minutes prior to each meal. After intraperitoneal insulin maximal plasma free insulin concentration was observed within 45 minutes of administration, and averaged 40±13 mU/l (±SEM) for breakfast, 30±13 mU/l for lunch, and 36±13 mU/l for supper. This acute rise was followed by a gradual decline in plasma free insulin concentration, simulating a normal plasma insulin profile. With subcutaneously injected insulin, approximately the same maximal plasma free insulin concentration was obtained as observed with intraperitoneal insulin, but it was delayed 116 minutes following injection. These data suggest that intraperitoneally delivered insulin is rapidly absorbed and may normalize the peripheral plasma free insulin concentration, at least during short-term studies.

The Regulation of Plasma Ketone Body Concentration by Counter-regulatory Hormones in Man: II. Effects of Growth Hormone in Diabetic Man

Growth hormone has classically been considered to be a diabetogenic hormone. However, in insulin-dependent diabetic man the mechanism of its ketogenic activity has not been resolved. Therefore, this study was designed to examine three aspects of growth hormones ketogenic activity: first, whether growth hormones ketogenic activity can be entirely accounted for by its lipolytic effect; second, whether growth hormones ketogenic activity is rapid or delayed in onset; and third, whether growth hormone may exert ketogenic activity indirectly by altering the plasma concentration of other ketone body-regulatory hormones (i.e. insulin, glucagon, and cortisol). In order to obtain data relative to these three questions, growth hormone was administered to six insulin dependent, ketosis-prone diabetic subjects. Both acute and prolonged growth hormone exposure studies were performed in all subjects and compared with a control study. Plasma free-fatty-acid concentration was elevated in all studies by heparin administration to assess growth hormones ketogenic activity independent of its lipolytic effect. Our results suggest that, in insulin-dependent diabetic man, growth hormone exerts profound ketogenic activity that is delayed at least 60 minutes. Although this ketogenic activity may be a direct effect of the hormone, our results indicate that at least two indirect mechanisms may participate in raising plasma ketone body concentration. First, growth hormone may exert ketogenic activity indirectly by elevating plasma free-fatty-acid substrate concentration. Second, growth hormone administration results in a significant reduction in circulating plasma free–insulin concentration, an observation that has not been previously reported. Since the diabetics in this study were given a fixed dose of exogenous insulin, these results suggest that growth hormone alters either the absorption and/or degradation of injected insulin in diabetic man. This latter mechanism may account for our observation that growth hormone exerts ketogenic activity independent of its lipolytic effect.

The Intravenous, Intraperitoneal, and Subcutaneous Routes of Insulin Delivery in Diabetic Man

Successful implantation of an artificial pancreas requires the infusion of insulin into an appropriate anatomic site. Three sites being actively investigated include (1) intravenous (i.V.), (2) intraperitoneal (i.p.), and (3) subcutaneous (s.c). This study compared the rate, magnitude, and duration of insulin absorption from these three absorption sites as assessed by the appearance of “free” insulin into the plasma of 10 insulin-dependent diabetic subjects. The biologic effectiveness of insulin was assessed by the suppression of plasma glucose concentration following a 750-calorie meal. Our results suggest that i.v. delivered insulin provides the most rapid increase in plasma free insulin concentration, followed by the i.p. and s.c. routes, respectively. In contrast, the elevation of plasma free insulin concentration was most prolonged with the s.c. route, followed by i.p. and i.v. routes, respectively. Compared with the i.v. and s.c. routes of insulin delivery, only 50% of the i.p. delivered insulin appeared in the plasma. The onset of the biologic activity of the insulin delivered by the three different routes during the 4½-h observation period was most rapid for the i.v. and least rapid for the s.c. route. These results suggest that all three routes may be appropriate sites for delivery of insulin from an artificial pancreas. However, because of the difference in absorption kinetics and the onset of biologic effectiveness of the delivered insulin, different quantities and timing of insulin delivery may be needed.

Pathogenesis of Diabetic Ketoacidosis: A Reappraisal

This study reviews the pathogenic hormonal abnormalities (insulin deficiency and stress hormone excess) in diabetic ketoacidosis. The data both supporting and negating a primary role for insulin deficiency in the pathogenesis of diabetic ketoacidosis are examined. Evidence implicating excess stress hormone secretion as a necessary event in the development of severe metabolic decompensation is discussed. The data suggest that diabetic ketoacidosis may be prevented by correcting either the relative deficiency of insulin or the excess secreation of one or a combination of the stress hormones. Studies supporting a primary role for insulin deficiency in the pathogenesis of diabetic ketoacidosis include the beneficial therapeutic response to insulin administration in ketoacidosis, development of ketoacidosis; and (3) stress hormone excess is necessary for fulminant ketoacidosis to be manifested.s following insulin withdrawal from diabetic man and animals, and hypoglycemic and hypoketonemic effects of insulin. Studies negating a primary role for insulin deficiency in ketoacidosis include the “normal” plasma insulin concentration in the majority of ketoacidotic cases, delayed onset of ketoacidosis after insulin withdrawal from diabetic man, and lack of hypolipolytic and hypoketonemic effect of insulin without prior stress hormone adipocyte and hepatocyte stimulation. Evidence that stress hormones (glucagon, catecholamines, cortisol, and growth hormone) contribute to the metabolic decompensation of ketoacidosis includes: (1) in all cases of ketoacidosis, at least one stress hormone is always elevated; (2) pharmacologic blockade of each of the stress hormones reduces the rate and/or frequency of metabolic decompensation in diabetic man; (3) removal of the pituitary and/or the adrenal gland in diabetic animals completely prevents the development of ketoacidosis after insulin withdrawal; and (4) administration of each of the four stress hormones under appropriate conditions induces metabolic decompensation in diabetic man with “normal” circulating levels of plasma insulin concentration. From these studies, the following conclusions are supported: (1) absolute insulin deficiency is an unusual cause of ketoacidosis; (2) the presence of relative insulin deficiency is necessary for the development of ketoacidosis; and (3) stress hormone excess is necessary for fulminant ketoacidosis to be manifested.

Normalization of plasma insulin profiles in diabetic subjects with programmed insulin delivery.

Normalization of plasma glucose concentration with subcutaneous injections of insulin has been difficult. With intravenous insulin delivery, normalization of plasma glucose concentration in adult-onset diabetic patients has been achieved when their plasma insulin concentration was normalized. In juvenile-onset diabetic subjects totally lacking endogenous insulin, the effect of normalization of the plasma insulin concentration has not yet been reported. In the present studies, the plasma insulin profile was normalized in four brittle, insulin-dependent diabetic subjects throughout three meals (breakfast, lunch, and supper). Plasma free insulin concentration was assayed after precipitation of endogenous insulin antibodies with polyethylene glycol. Acute meal-related increases in plasma free insulin concentration were achieved with a programmable intravenous insulin delivery system. When plasma insulin profiles were normalized in insulin-dependent diabetic subjects lacking endogenous insulin secretion, an improvement in meal-related glucose excursions was observed. However, complete normalization of plasma glucose concentration was not achieved, suggesting that factors other than plasma insulin concentration modulate carbohydrate homeostasis in brittle diabetes. These factors may include portal vein hypoinsulinemia during peripheral vein insulin infusion, stress hormone concentrations, and tissue insulin resistance.

Structure-function relationships within peripheral nerves in diabetic neuropathy : the hydration hypothesis

SummaryTo define the quantitative relationship between peripheral nerve structure and function imposed by endoneurial oedema in the diabetic state, we determined values for sural nerve hydration structure as measured by magnetic resonance spectroscopy, and for neurological function with scores for nerve conduction properties (NCV-score), neuropathic symptoms (NS-score), and examination signs (NE-score). The coefficient of sural nerve hydration was elevated to 30±6% (p<0.05) in 79 symptomatic neuropathic diabetic subjects with an average of 15 years of diabetes mellitus, compared to a value of 25±3% in 72 non-diabetic control subjects. In contrast, in 75 asymptomatic diabetic subjects with an average of 6 additional years of diabetes, the mean hydration coefficient was only 28±5% (p<0.05). A nerve hyperhydration state was identified with a prevalence of 25% within the asymptomatic group characterized by nerve hydration greater than the 95th percentile, early changes in nerve electrophysiology and neurological examination, but with no symptomatology of neuropathy. Stratification of the symptomatic neuropathic group by worsening nerve electrophysiology, demonstrates a coincident deterioration in neurological examination (RR=5.39 at maximum NCV-score), and neuropathy symptomatology (RR=4.80 at maximum NE-score). The present data are consistent with the hypothesis that endoneurial oedema initiates deterioration sequentially in nerve electrophysiology, followed by abnormal findings on neurological examination, preceding the patients final perception of symptomatic stocking-glove peripheral diabetic neuropathy.

Catheter Survival During Long-Term Insulin Therapy With an Implanted Programmable Pump

OBJECTIVE To survey catheter complications and to analyze catheter survival during long-term intraperitoneal and intravenous insulin therapy with an implanted programmable pump with a sideport. RESEARCH DESIGN AND METHODS Catheter occlusions were documented by measuring dynamic catheter resistance. Catheter migrations or breaks were demonstrated by × ray. When flushing the catheter with buffer solution through the sideport failed to clear the occlusion, catheters were replaced or laparoscopy was performed for the excision of fibrous tissue growth. Broken or migrated catheters were replaced. RESULTS Occlusions were the most common catheter complications, and the majority of them (79% intraperitoneal and 84% intravenous) were cleared by flushing the catheter. Survival at 3 years was significantly higher for intraperitoneal catheters compared with intravenous catheters (60% intraperitoneal and 22% intravenous). CONCLUSIONS Nonsurgical management of catheter occlusions contributed to extend catheter lifetime. Intraperitoneal catheters have a lower morbidity and a higher survival than intravenous catheters.

Diabetic Glucose Control: Matching Plasma Insulin Concentration to Dietary and Stress Hyperglycemia

Optimal management of the diabetic patient includes normalization of plasma glucose concentration. Attainment of this goal is difficult because both food and stress result in acute elevations of blood glucose that cannot be matched with a single subcutaneous injection of NPH insulin. This paper examines the currently available methods for delivery of insulin to the diabetic subject and the degree of metabolic control attained. It suggests that optimal diabetic control will be achieved only when newer methods of insulin delivery are available to the clinician that match plasma insulin requirements to the simultaneous plasma glucose concentration.

Future Therapy of the Insulin-dependent Diabetic Patient—The Implantable Insulin Delivery System

An implantable insulin delivery system has several advantages not shared by currently available, portable external delivery devices. First, since the implantable system does not come in contact with the external environment, insulin delivery routes other than the subcutaneous tissue may be utilized without the danger of infection. These alternative routes may provide more rapid insulin absorption, enhanced hepatic insulinization, and improved diabetic control for “C”-peptide-negative brittle diabetic patients. Second, the implantable system is protected from external trauma, permitting a wider range of daily activities and sporting events. Third, the implantable system is easily concealed by clothing, thereby increasing patient acceptance of it. However, an implantable system also has disadvantages. First, surgery will be required to implant or explant the pump module and reservoir, and second, the implanted system must be highly reliable and include failsafe mechanisms to insure the safety of the recipient. These advantages and disadvantages have resulted in delineation of general specifications for an inv plantable insulin delivery system. Desirable features of an implantable insulin delivery system include (1) reliability and failsafe operation, (2) being implantable and explantable under local anesthesia, (3) long battery life, (4) multiple insulin delivery rates, (5) small size and weight, (6) biocompatible materials, (7) remote programmability based upon recipient blood glucose monitoring, and (8) ability to deliver concentrated insulin with infrequent reservoir refilling. Using available technology, each of these specifications has been incorporated into the functioning of our current implant system, which is being tested in diabetic dogs. Future experiments in man will undoubtedly alter and add to the current specifications.