Intensive glucose control and macrovascular outcomes in type 2 diabetes.

AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report.

OBJECTIVE: The Veterans Affairs Diabetes Trial (VADT) will assess the effect of intensive (INT) vs improved standard (STD) glycaemic control on major cardiovascular (CV) events, treating other risk factors equally in both arms. Four-year results of main metabolic parameters are presented. RESEARCH DESIGN AND METHODS: VADT is a 7.5 years prospective randomized study of 1791 patients, 20 centres, of men and women of age 60.5 +/- 8.7 years, diagnosed for 11.5 +/- 7.5 years. Their body mass index (BMI) at baseline was 31 +/- 4 kg/m(2) and mean A1C 9.4 +/- 1.5% after maximum dose of oral agents or insulin treatment. Step treatment consists of glimepiride or metformin, rosiglitazone, insulin and other agents; A1C goals are 8-9% in STD and <6% in INT. Lifestyle, blood pressure and lipids are treated uniformly in both arms. RESULTS: A1C improved in both arms. INT kept median A1C <7% all years, A1C separation is 1.5-1.7%. From year 1 to 4, mean blood pressure is <129/74 mmHg, similar throughout. Median LDL-C was <97 mg/dl by year 1 and triglycerides 150 or less by 2 years. Triglycerides were lower in INT (12-16 mg/dl; p < 0.01). By 4 years, 88% are on lipid-lowering agents and 93% are on antiplatelet/anticoagulant agents. BMI is higher in INT every year (0.9-1.6 kg/m(2); p < 0.01). CONCLUSION: VADT is maintaining the expected A1C in both STD and INT, and LDL-C, triglycerides and blood pressure are at target. The trial is continuing to June 2008. It will be the first long-term completed type 2 diabetes study of the role of glycaemia on CV disease with modern treatments.

Insulin degradation: mechanisms, products, and significance.

Although much remains to be learned, our understanding of the mechanisms and processes by which insulin is degraded has advanced considerably over the past few years. The roles of receptor binding and internalization in mediating insulin degradation have been clarified, and the endosomal pathway for intracellular insulin degradation has been established and partially characterized. The importance of IP (IDE) in cellular insulin degradation has been established and the importance of lysosomal degradation questioned. Studies on IP have identified the degradation products resulting from insulin metabolism by this enzyme and shown that the degradation products by IP are identical with those produced by isolated hepatocytes. A major remaining question for future investigation is the potential role of insulin degradation and intracellular processing in insulin action.

Recombinant DNA technology in the treatment of diabetes: insulin analogs.

After more than half a century of treating diabetics with animal insulins, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogs were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid-, intermediate-, and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analog, lispro, confirmed the hopes by showing that improved glycemic control can be achieved without an increase in hypoglycemic events. Two new insulin analogs, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States, and several other analogs are being intensively tested. Thus, it appears that a rapid acceleration of basic and clinical research in this arena will be seen, which will have direct significance to both patients and their physicians. The introduction of new short-acting analogs and the development of the first truly long-acting analogs and the development of analogs with increased stability, less variability, and perhaps selective action, will help to develop more individualized treatment strategies targeted to specific patient characteristics and to achieve further improvements in glycemic control. Data on the currently available and tested analogs, as well as data on those currently being developed, are reviewed.

Insulin degradation: progress and potential.

Insulin degradation is a regulated process that plays a role in controlling insulin action by removing and inactivating the hormone. Abnormalities in insulin clearance and degradation are present in various pathological conditions including type 2 diabetes and obesity and may be important in producing clinical problems. The uptake, processing, and degradation of insulin by cells is a complex process with multiple intracellular pathways. Most evidence supports IDE as the primary degradative mechanism, but other systems (PDI, lysosomes, and other enzymes) undoubtedly contribute to insulin metabolism. Recent studies support a multifunctional role for IDE, as an intracellular binding, regulatory, and degradative protein. IDE increases proteasome and steroid hormone receptor activity, and this activation is reversed by insulin. This raises the possibility of a direct intracellular interaction of insulin with IDE that could modulate protein and fat metabolism. The recent findings would place intracellular insulin-IDE interaction into the insulin signal transduction pathway for mediating the intermediate effects of insulin on fat and protein turnover.

Simulated hyperglycemic hyperosmolar syndrome. Impaired insulin and epinephrine effects upon lipolysis in the isolated rat fat cell.

These investigations were designed to evaluate the effect of excess glucose and sodium chloride on lipolysis in the isolated adipocyte under normal and modelled pathological conditions simulating the hyperglycemic hyperosmolar syndrome. Isolated rat fat cells were incubated in the presence of various combinations of sodium chloride, glucose, epinephrine, and insulin. Lipolysis was measured as glycerol and free fatty acid release, and total medium osmolarity as milliosmoles per liter by freezing point depression. Basal lipolysis was unaffected by changes in osmolarity with sodium chloride, but glucose and glucose plus sodium chloride increased basal glycerol release. Increasing osmolarity with sodium chloride diminished the lipolytic response to epinephrine. Increasing osmolarity with glucose augmented the lipolytic response to epinephrine up to a total medium osmolarity of 550 mosmol. Higher osmolarities produced with glucose suppressed the epinephrine-induced lipolytic response.When the hyperglycemic hyperosmolar syndrome was simulated with 100 mM glucose and 50 mM sodium chloride (total osmolarity = 460 mosmol) the epinephrine-stimulated lipolysis dose-response curve in the isolated fat cell was shifted to the right. Furthermore, in the presence of 100 mM glucose + 50 mM sodium chloride, physiological concentrations of insulin were less effective in opposing epinephrine-stimulated lipolysis. In the presence of 50 mM glucose and 25 mM sodium chloride (total osmolarity = 370 mosmol) epinephrine-stimulated lipolysis measured as free fatty acid release was decreased by 50%. Under conditions simulating the hyperglycemic hyperosmolar syndrome in the isolated rat adipocyte, altered lipolysis reflects impaired effectiveness of both insulin and epinephrine as antilipolytic and lipolytic hormones, respectively. Furthermore, the attenuated response to both hormones appears to be primarily a function of extracellular solute composition. The lack of ketosis is the result of diminished release of free fatty acids from peripheral adipose cells.

Time-course of insulin degradation in perifused isolated rat adipose cells.

Isolated fat cells from rat epididymal adipose tissue were preincubated with 50 microU/ml (0.33 nM) 125I-insulin at 23 degrees C to enhance binding while retarding degradation. The fat cells were then perifused at that temperature to remove unbound 125I-insulin, and fractions of perifusate were collected each minute. The temperature of the cells in the perifusion chamber was then rapidly increased to 37 degrees C, and perifusion was continued. The fat cells degraded a portion of the bound 125I-insulin measured by loss of immunoprecipitability with excess antisera to insulin. The percentage of degraded 125I-insulin dissociating from the fat cells increased progressively with time at 37 degrees C, and the rateof dissociation of 125I-insulin degradation products showed a first-order dependence on the amount of degraded 125I-insulin bound to the cells. To explain this first-order dependence it is necessary to postulate a "processing" step after binding and before degradation. The first-order rate constant at 37 degrees C is 0.023 +/- 0.004 min-1. Fast and slow dissociating components can be resolved from kinetic plots of the dissociation of undegraded 125I-insulin (immunoprecipitable) from the isolated fat cells. The antilipolytic activity of the 125I-insulin on epinephrine-stimulated lipolysis is evident over much of the time-course of dissociation. A model for the degradation of insulin bound to isolated fat cells is discussed.

Perifusion of isolated rat adipose cells. Modulation of lipolysis by adenosine.

Incubation of isolated rat epididymal fat cells is associated with the accumulation of adenosine in the incubation medium. To more clearly define the effect of adenosine on lipolysis, isolated rat epididymal adipocytes were studied with the perifusion system. Various combinations of epinephrine, adenosine, and adenosine deaminase were perifused through the adipocytes. Exogenous adenosine, 0.001-10.0 muM, had no discernible influence upon unstimulated lipolysis; but exogenous adenosine inhibited epinephrine-sensitive lipolysis in a concentration-dependent manner. Cells perifused with 0.3 muM epinephrine plus 0.001 muM adenosine did not show any impairment of the lipolytic response to 0.3 muM epinephrine alone. Adenosine, 0.01 muM, inhibited the response to epinephrine by 50%; response to 0.3 muM epinephrine plus 0.1 muM adenosine was similar to the basal rate. Perifusion with adenosine deaminase significantly increased basal lipolysis to 30% of the epinephrine response. Adenosine deaminase and epinephrine were synergistic in stimulating lipolysis to 180% of the response to epinephrine alone. Isolated fat cells were incubated for 30 min, and the cell-free used medium was perifused through fresh fat cells. Epinephrine in used medium was less effective in promoting lipolysis than epinephrine in fresh buffer. High-pressure liquid chromatography identified adenosine in the used medium. Bovine serum albumin possessed adenosine deaminase activity but accounted for negligible conversion of adenosine to inosine. Adenosine is shown to have a modulating effect upon basal and hormone-stimulated lipolysis in the perifusion system. Sufficient endogenous adenosine (<0.01 muM) is present to maximally affect basal lipolysis. Hormone-stimulated lipolysis, although inhibited somewhat by endogenous adenosine, requires the addition of exogenous adenosine for complete inhibition.

Direct measurement of proinsulin in human plasma by the use of an insulin-degrading enzyme.

A method has been described for the direct measurement of proinsulin in human plasma. The method makes use of an insulin-degrading enzyme designated "insulin-specific protease (ISP)", which is obtained from rat skeletal muscle. Under the conditions used, this enzyme rapidly degrades insulin and insulin-like polypeptides to nonimmunoassayable components, whereas proinsulin and proinsulin cleaved at position B(54,55) are not appreciably affected. The incubation of plasma with ISP results in the disappearance of insulin, but not proinsulin, as demonstrated by column chromatography. Immunoassay of the plasma, therefore, before and after incubation, determines the values for the total immunoreactive substance (TIR) and for immunoreactive proinsulin (IRP), respectively. The values obtained for proinsulin levels are reproducible and compare closely with the more complicated column fractionation methods. Proinsulin responses were studied in four normal subjects and one patient with an insulinoma after a glucose load. Fasting proinsulin levels varied widely in the normal subjects, and the levels rose more slowly than TIR levels after glucose. IRP levels in the patient with an insulinoma were very high and fell to normal after removal of the tumor. The ISP method, therefore, appears to be suitable for the direct, accurate, and rapid determination of proinsulin and proinsulin-like materials in human plasma.

Increased clearance and degradation of [3H]insulin in streptozotocin diabetic rats.

The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since streptozotocin-diabetes in rats results in increased insulin binding to tissues in vitro, insulin pharmacokinetics in streptozotocin-diabetic rats were compared to controls, using semisynthetic [(3)H]insulin as the tracer. The initial distribution volume for [(3)H]insulin was elevated by 60% in diabetic rats. By contrast, no difference in initial distribution volume for [(14)C]inulin was observed, and the absolute values were lower than those found for [(3)H]insulin. The metabolic clearance rate of [(3)H]insulin was elevated by 44% in diabetic rats. That these differences were the result of increased binding of insulin to a specific receptor compartment in diabetic rats was shown by three additional experiments. The first involved receptor saturation by injection of 10 U native insulin 2 min before the tracer injection, resulting in identical [(3)H]insulin disappearance rates in the two groups of rats. The second consisted of displacing [(3)H]insulin from receptors by injecting 10 U unlabeled insulin 6 min after the tracer injection. Displacement of intact [(3)H]insulin from receptors and subsequent reappearance in the circulation occurred in both control and diabetic animals; however, such displacement was 25% greater in the diabetic rats. Finally, treatment of diabetic rats with insulin for 8 d normalized [(3)H]insulin clearance even though the tracer was injected at a time when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance.

Inhibition of insulin degradation by nonsuppressible insulin-like activity.

Nonsuppressible insulin-like activity, provided by three sources, was evaluated for its effect on the proteolytic degradation of insulin utilizing insulin protease obtained from rat liver homogenate as well as liver cell membranes. All three preparations of nonsuppressible insulin-like activity were found to be competitive inhibitors of insulin degradation. In addition human plasma was fractionated yielding an acetone precipitate which was found to have nonsuppressible insulin-like activity and to be a competitive inhibitor of insulin protease.

Insulin and glucagon degradation by the kidney. I. Subcellular distribution under different assay condition.

Insulin and glucagon degradation by rat kidney homogenates and subcellular fractions was examined under a variety of conditions including high and low substrate concentrations, at pH 4 and pH 7, with and without glutathione. At high insulin concentration (4.1 - 10(-5) M) insulin degradation by the homogenate was greatest at pH 4 but at low insulin concentration (1 - 10(-10) M) insulin degradation was greatest at pH 7. At either high or low glucagon concentration glucagon degradation by the homogenate was greatest at pH 7. Glutathione at pH 7 stimulated insulin degradation at high insulin concentrations and inhibited insulin degradation at low concentrations; Glucagon degradation at pH 7 was inhibited at both high and low concentrations of glucagon by glutathionemseparation of kidney into cortex and medulla prior to homogenation produced a pattern of insulin and glucagon degradation identical to the whole homogenate but glucagon degradation by the medulla was greater than by the cortex. Examination of degradation by subcellular fractions revealed that at high concentration at neutral pH most insulin was degraded by the 100 000 X g pellet but at low insulin concentrations over 90% of the activity was in the 100 000 X g supernatant; At pH 7, at both high and low concentrations, most glucagon-degrading activity was in the 100 000 X g pellet, although the cytosol also had activity; At pH 4 most degradation occurred in the lysosomal fractions. Separation into cortex and medulla again showed similar distribution of activity as the whole gland with the medulla having more glucagon-degrading activity than the cortex. With low insulin concentrations the cortex 100 000 X g supernatant had higher relative specific activities than the medulla supernatant. Examination of recoveries of enzyme activity revealed that the subcellular fractions consistently had markedly less insulin-degrading activity than the original homogenate. This loss of activity was only discernible when insulin degradation was performed at pH 7 at low substrate concentrations. Comparable losses of glucagon-degrading activity were not seen.

Insulin and glucagon degradation by the kidney. II. Characterization of the mechanisms at neutral pH.

Examination of insulin and glucagon degradation by rat kidney subcellular fractions revealed that most degrading activity was localized to the 100 000 X g pellet and 100 000 X g supernatant fractions. Further characterization of the degrading activities of the 100 000 X g pellet and supernatant suggested that three types of enzymatic activity were present at neutral pH. From the cytosol an enzyme with characteristics of the insulin glucagon protease of skeletal muscle was purified. This enzyme appeared to be responsible for insulin degradation by the kidney at physiological insulin concentrations. This enzyme also contributed to glucagon degradation but was not the most active mechanism for this. In the 100 000 X g pellet at least two separate enzymatic activities were present. One of these had properties consistent with those described for glutathione insulin transhydrogenase and appeared to be responsible for insulin degradation at high insulin concentration. The other enzyme was associated with the brush border and had properties consistent with the brush border neutral protease. This enzyme appeared responsible for glucagon degradation at both low and high substrate concentrations. An apparent marked synergism between the 100 000 X g pellet and the 100 000 X g supernatant was noted for insulin degradation at physiological insulin concentrations. Pellet glucagon-degrading activity and soluble insulin-degrading activity were necessary for this. The mechanism was found to be limited insulin degradation by the soluble enzyme resulting in both trichloroacetic acid-precipitable trichloroacetic acid-soluble fragments followed by further degradtion of the fragments by the glucagon-degrading enzyme resulting in an additional increase in trichloroacetic acid-soluble products.

Proteolytic degradation of insulin and glucagon.

The degradation of insulin and glucagon by a highly purified enzyme isolated from rat skeletal muscle was investigated. A sensitive assay for proteolytic degradation of insulin and glucagon using fluorescamine to detect an increase in primary amine groups was established. As measured by an increase in fluorescamine reactive materials, insulin was rapidly degraded by this highly purified enzyme without requiring initial disulfide cleavage. Associated with the increase in fluorescamine reactive materials was a decrease in immunoassayable insulinmglucagon wal also proteolytically degraded by this enzyme but a number of other peptides and proteins including proinsulin, and A and B chains of insulin were not degraded. Thus, we have demonstrated that insulin (and glucagon) can be proteolytically degraded by an enzyme isolated from an insulin sensitive tissue, skeletal muscle. Proteolytic degradation by this enzyme requires the intact insulin molecule rather than separate A and B chains.

Identification of the cleavage sites of transforming growth factor alpha by insulin-degrading enzymes.

Insulin-degrading enzyme (IDE) is a sulfhydryl-dependent metalloproteinase with a zinc binding site unique to a new class of proteinases. The enzyme is relatively specific for a number of hormones/growth factors, such as insulin, atrial natriuretic peptide, IGF-II, and proinsulin. In this study we have identified the amino-acid bonds cleaved by IDE in transforming growth factor-alpha. High-performance liquid chromatography was used to separate the peptides generated by the degradation of 125I-TGF-alpha. The peptides were then submitted to sequential Edman degradation to determine the peptide bond broken. Cleavage sites were found at amino acids, 10-11 (Asp-Ser), 25-26 (Val-Gln), 28-29 (Asp-Lys), and 30-31 (Pro-Ala). In agreement with studies of cleavage sites of other hormones by this enzyme, no clear amino-acid specificity was seen. However, examination of the sites on a three-dimensional model of TGF-alpha suggest the primary mechanism used by IDE for determining cleavage sites is the tertiary structure of the substrate.

Two pathways for insulin metabolism in adipocytes.

Using selected conditions, the appropriate collagenase, albumin and cell treatment, a preparation of isolated adipocytes was developed with no extracellular insulin degrading activity. Cell mediated insulin degradation rates were 0.68% +/- 0.05%/100,000 cell/h using trichloracetic acid precipitability as a measure. Chloroquine (CQ) increased cell-associated radioactivity and decreased degradation while dansylcadaverine (DC), PCMBS and bacitracin (BAC) decreased degradation with no effect on binding. Extraction and chromatography of the cell-associated radioactivity showed 3 peaks, a large molecular weight peak, a small molecular weight peak and an insulin-sized peak. CQ, DC and BAC all decreased the small molecular weight peak while CQ and DC also increased the peak of large molecular weight radioactivity. Cell mediated insulin degradation in the presence of combinations of inhibitors suggested two pathways in adipocytes, one affected by inhibitors of the insulin degrading enzyme (IDE) (bacitracin and PCMBS) and the other altered by cell processing inhibitors (DC, CQ and phenylarsenoxide). Chloroquine altered the pattern of the insulin-sized cell-associated HPLC assayed degradation products, further supporting two pathways of degradation; one a chloroquine-sensitive and one a chloroquine-insensitive pathway.

The reversible inhibition by carbonyl cyanide m-chlorophenyl hydrazone of epinephrine-stimulated lipolysis in perifused isolated fat cells.

Lipolysis stimulated in perifused isolated fat cells by 0.5 micrometers epinephrine is an ATP-dependent process which can be monitored by measuring the release of glycerol. The stimulated lipolysis is inhibited to 10 micrometers carbonyl cyanide m-chlorophenyl hydrazone (CCCP), an uncoupler of oxidative phosphorylation. If 20-micrometers glucose is continuously present in the perifusion medium during and after treatment with epinephrine and CCCP, the inhibition of the stimulated lipolysis is reversible when the CCCP is discontinued; otherwise it is not readily reversible. Since 20 micrometers 2-deoxyglucose will not substitute for glucose, metabolism of glucose beyond phosphorylation by hexokinase is concluded to be necessary in order to maintain the reversibility of the inhibition of CCCP. Substitution of 10 micrometers succinate for glucose also did not preserve the reversibility of the CCCP inhibition, and there was no significant difference in the amount of decrease of ATP in fat cells incubated with CCCP and epinephrine in the presence of glucose as compared to the decrease observed in the presence of succinate. The mechanism by which glucose maintains reversibility of the inhibition of stimulated lipolysis by CCCP is therefore not clear.

HPLC analysis of insulin degradation products from isolated hepatocytes. Effects of inhibitors suggest intracellular and extracellular pathways.

Isolated rat hepatocytes were incubated with A14-[125I]monoiodotyrosyl insulin for 30 min, and labeled material was extracted from the cells and incubation media. The medium and the cell extract were chromatographed on a Sephadex G-50 column, and radioactivity eluting in the position of intact insulin was concentrated and analyzed on HPLC. The HPLC analysis of the cell extract showed two major products eluting from the column at 19 and 23 min, whereas medium extracts showed one prominent product eluting at 14 min. Inclusion of chloroquine in the incubation blocked the formation of cellular products at 19 and 23 min and caused the accumulation of a product eluting at 41 min while not affecting the media products. After sulfitolysis all cellular products contained an intact A-chain. Dansylcadaverine increased media products and altered the cell-extracted product pattern such that it had a major peak at 14 min, similar to media. These results suggest that two pathways for insulin degradation exist within hepatocytes. The extracellular process forms products that are essentially unchanged by chloroquine and dansylcadaverine. The intracellular process is altered by chloroquine and apparently inhibited by dansylcadaverine.

In vitro activity of biosynthetic human proinsulin. Receptor binding and biologic potency of proinsulin and insulin in isolated rat adipocytes.

The receptor binding characteristics and biologic protency of biosynthetic human proinsulin (rDNA) were determined in isolated rat adipocytes and compared with those of insulin. In competition with 125I(A14)-iodoinsulin for binding to adipocyte receptors at 15 degrees C, proinsulin showed a 100-fold lower affinity for binding than did insulin. A proinsulin concentration of 3.2 +/- 0.8 X 10(-7) M was required for 50% inhibition of tracer binding as compared with a concentration of 1.7 +/- 0.3 X 10(-9) M for insulin. These results were confirmed in direct competition studies using proinsulin and 125I-iodoproinsulin. A similar 100-fold difference was also observed in competitive binding experiments conducted at 37 degrees C. The biologic potency of human proinsulin was evaluated by its ability to stimulate glucose incorporation into total fat cell lipid and also by its antilipolytic activity. Glucose incorporation into lipid was half-maximal at a proinsulin concentration of 1.5 +/- 0.4 X 10(-8) M, whereas the same response was observed at an insulin concentration of 5.2 +/- 1 X 10(-11) M. Proinsulin also demonstrated an antilipolytic potency that was less than 1% that of insulin. The time course over which insulin and proinsulin stimulated glucose incorporation into lipid was the same, as was the time course over which the stimulation dissipated after removal of the hormones. No synergism of insulin and proinsulin stimulation of lipogenesis was observed when fat cells were incubated with submaximal concentrations of the two hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Why intraperitoneal delivery of insulin with implantable pumps in NIDDM?

In the normal state, pancreatic secretion of insulin results in a portal/peripheral gradient with the highest concentrations of insulin in the liver. In diabetic patients with absent or insufficient pancreatic insulin secretion who require exogenous insulin, this normal gradient is lost, resulting in numerous abnormalities. This consideration led to interest in the intraperitoneal delivery of insulin, hoping to produce a therapeutic state more closely resembling normal physiology. The development of implantable insulin pumps, which can deliver insulin intraperitoneally, led to numerous studies on insulin-dependent diabetes mellitus (IDDM) patients, demonstrating that insulin delivered intraperitoneally is rapidly and predictably absorbed with most of it going into the portal system, resulting in hepatic delivery of insulin. Studies in IDDM patients have demonstrated that good glucose control can be achieved with intraperitoneal delivery of insulin from implantable pumps with lesser glycemic fluctuations and, therefore, fewer episodes of hypoglycemia. Furthermore, intraperitoneal insulin results in carbohydrate and particularly lipid metabolism that more closely mimics the normal physiological state than produced by injections of insulin. Thus, implantable insulin pumps are being studied for use in IDDM. Many non-insulin-dependent diabetes mellitus (NIDDM) patients have insufficient pancreatic secretion and require exogenous insulin. Because of alterations in hepatic sensitivity to insulin, increments in insulin delivery to the liver may be even more important in NIDDM than IDDM. Furthermore, insulin resistance, which is an integral part of NIDDM, results in higher physiological levels of insulin, which are required for glucose control, and thus significant peripheral hyperinsulinemia occurs in patients receiving exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)