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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that specific binding sites for insulin are present on the plasma membranes of target tissues. In order to explain how insulin regulates a wide variety of biologic functions both on the surface of the cell as well as in its interior, it has been postulated that insulin generates a second messenger at the cell surface. To date, however, no second messenger for insulin has been identified that can carry out all of insulin's known actions. Recent studies have demonstrated that, in addition to the plasma membrane, other subcellular organelles, such as the nucleus, have specific binding sites for insulin. There is also evidence indicating that large serum proteins such as albumin, large protein hormones such as prolactin, and small protein hormones such as insulin can enter intact cells. It is hypothesized, therefore, that insulin has at least two mechanisms of action on target tissues. One mechanism entails the direct binding of insulin to the plasma membrane, which in turn leads to its well-known effects on membrane transport. The other mechanism requires the entry of insulin itself into the interior of the cell and its subsequent direct binding to subcellular organelles. This latter process then serves to mediate many of the known intracellular functions of insulin.
Diabetes 1977 Feb
PMID:Does insulin need a second messenger? 32 74

One month following a cadaver renal transplant for obstructive uropathy, a 27-year-old man developed diabetes mellitus. Two years later, marked proteinuria and decreased renal function were detected. Eight months later, a second decline in function occurred. Light microscopy of graft biopsy specimens obtained after each decline in renal function showed increased mesangial cells and matrix, thickening of Bowman capsule, and tubular atrophy with basement membrane thickening. Vascular changes, interstitial infiltrate, and fibrosis were not prominent. Electron microscopic studies of the second biopsy specimen confirmed the light microscopic changes; subepithelial dense deposits were also detected. Immunofluorescent studies of both biopsy specimens demonstrated linear staining of glomerular and tubular basement membranes and Bowman capsule for IgG and albumin. Antikidney antibodies were not detected in the patient's serum. These observations suggest development of the diffuse form of diabetic nephropathy in a renal homograft following steroid-induced diabetes mellitus.
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PMID:Development of a lesion resembling diabetic nephropathy in a renal homograft. 32 61

Metabolic disorders and immunological factors are discussed in connection with the pathogenesis of diabetic microangiopathy. Renal biopsies were obtained from 22 diabetics (8 women aged 18 to 53, 14 men aged 15 to 52). 7 of the 22 patients had been suffering from diabetes for 2 weeks to 3 years, 10 for 7 to 25 years, 2 showed a pathological glucose-tolerance test, i.e., they had been "latent" diabetics, and 3 patients, had been so-called "potential" subjects of diabetes due to hereditary traits or delivery of big babies. They were examined by light miroscopy as well as by immunofluorescence microscopy. A number of cases were chosen for the differentiation and counting of glomerular cells (n=8) as well as for electron microscopic (n=7) and polarizing-microscopic (n=6) examinations. Histologically, focal proliferations of mesangial cells as well as an increase in mesangial substance in the glomeruli was found in all cases, although in a varying degree of intensity. These results were confirmed by both the glomuerular cell count and electron-microscopic examination. Immunofluorescence microscopy made it possible to detect frequently both IgA (9/17) and IgG (9/17), usually in either linear or mesangial arrangements whereas it was less frequently possible to detect IgM (1/17) and albumin (1/8) and impossible to detect beta1C in the glomerulus. Labeled insulin was detected five times in the glomerulus. Polarizing-microscopic measurements made in order to discover possible submicroscopic variations in the structure of GBM showed deviations in the average values of anisotropic indices from the controls in the group of long-term diabetics only. The pathogenesis of diabetic microangiopathy may be described as an inflow of immunoglobulins and serum proteins into the mesangium because of an alteration of the capillary endothelium, the mesangial cell being thus caused to overfunction, proliferate and produce an excess of mesangial matrix. In prolonged diabetes the mesangial cell, so far as its own metabolism is concerned, will finally be affected to the point where its power of synthesis is modified in the sense of an excess and/or faulty composition of GBM (glomerular basement membrane).
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PMID:Renal biopsies performed on diabetics. 33 62

Kidney function was studied in six normal males before and during a 2 h glucagon (10 ng/kg/min) infusion. The following variables were determined during each 20 min clearance period; glomerular filtration rate (GFR), renal plasma-flow (RPF) , filtration fraction (FF), urinary albumin and beta2-microglobulin-excretion rates. Glucagon infusion resulted in a fourfold increase in plasma glucagon concentration. The infusion induced a significant increase in GFR (+9%), FF (+9%) and urinary beta2-microglobulin excretion rate (+32%), (p less than 0.01). RPF and urinary albumin excretion rates were not significantly changed. We suggest that glucagon may contribute to the reversible kidney function alterations typically found in poorly regulated juvenile diabetes, a state with relative or absolute hyperglucagonaemia.
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PMID:The effect of short-term glucagon infusion on kidney function in normal man. 33 17

Renal biopsies obtained from 22 patients with diabetes (8 women, mean age 38.5 years; 14 men, mean age 27.3 years)--including patients with potential, latent, short-term, and long-term diabetes--were examined by light microscopy as well as by immunofluorescence microscopy. Histologically, segmental and focal proliferation of mesangial cells as well as a mesangial broadening and an increase of substance deposited in the mesangium was found. These findings well documented by cell counting an differentiation are described in detail elsewhere (see Sorger et al. 1976 Immunhistochemically, we detected most frequently IgA (9/17) and IgG(9/17), usually in a linear or mesangial pattern, less frequently IgM (1/17). We failed to detect beta 1C and IgE in the glomerulus. Labeled insulin was demonstrated 5 times. Out of the plasmaproteins albumin, fibrinogen, transferrin, and beta-lipoproteid only albumin was perceptable. We consider the deposition of immunglogulins and serum-proteins in the glomerular filter to be an unspecific stimulation of proliferation of the mesangial cells being caused by overfunction and obviously produce an excess of the mesangial matrix.
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PMID:[Immunohistochemical findings in renal biopsies performed on diabetics (author's transl)]. 33 12

Skeletal muscle from 34 insulin-dependent diabetic patients and 20 age-matched controls was examined by immunofluorescent microscopy. Significantly increased staining of capillary and muscle basement membranes of diabetics was seen for IgG, albumin, and fibrin. The immunofluorescent pattern was identical with that observed using heterologous antibasement membrane antiserum, indicating that these proteins were present within these basement membranes. No differences were detected between males and females or between kidney-transplanted and nontransplanted diabetics. No correlation was noted between intensity of staining and duration of diabetes. The presence of certain serum proteins within vascular and nonvascular basement membranes in diabetics is not restricted to the kidney and may reflect widespread alterations in extracellular membranes that permit entrapment of these proteins.
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PMID:Immunofluorescence studies of skeletal muscle extracellular membranes in diabetes mellitus. 35 23

In order to examine the permeability of microvessels in diabetic children, the glomerular filtration rate, urinary excretion rates of albumin and beta 2-microglobulin, intravascular mass of albumin, and transcapillary escape rate of albumin were studied in 26 diabetic children without clinical signs of microangiopathy (age: 7-14 years; duration of disease: 3-14 years). Similar measurements were made in 28 healthy school children (age: 8-14 years). Mean glomerular filtration rate in the diabetic children was higher than in the normal children (138 versus 109 ml/min per 1.73 m2, p less than 0.01). Urinary excretion rates of albumin and beta 2-microglobulin did not differ in diabetics. Mean intravascular albumin mass in the diabetic girls (1.64 g/kg body weight) was lower (p less than 0.01) than in the diabetic boys (1.89 g/kg body weight) and also lower (p less than 0.02) than in the normal girls (1.94 g/kg body weight). Mean transcapillary escape rate of albumin in the twenty diabetics with duration of diabetes less than 10 years (7.14%/h) was lower (p less than 0.01) than that in normal children (8.90%/h); the escape rate showed a positive correlation with duration of diabetes (r=0.47; p less than 0.02). Thus glomerular filtration rate in diabetic children is elevated to the same extent as in adult short-term juvenile diabetics while the permeability of the glomerular membrane to macromolecules is normal. Interpretation of the results on intravascular albumin mass and transcapillary escape rate of albumin requires further investigation.
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PMID:Microvascular permeability to albumin and glomerular filtration rate in diabetic and normal children. 37 40

Insulin-degrading activity was measured in the 100,000g supernatant fraction of muscle, liver, and kidney from rats of varying ages. Young animals (four weeks old) had the highest activity in all three tissues. By seven weeks of age the activity in both muscle and liver had decreased significantly as compared with four-week-old animals. A slight but nonsignificant decrease occurred in kidney. In animals over one year of age the insulin-degrading activity in all three tissues was significantly less than the activities at either four or seven weeks. In contrast the effect of age on degradation of albumin and parathormone was much less marked.
Diabetes 1979 Apr
PMID:The effect of age on insulin-degrading activity in rat tissue. 43 72

Mitochondrial and peroxisomal fatty acid oxidation were compared in whole liver homogenates. Oxidation of 0.2 mM palmitoyl-CoA or oleate by mitochondria increased rapidly with increasing molar substrate:albumin ratios and became saturated at ratios below 3, while peroxisomal oxidation increased more slowly and continued to rise to reach maximal activity in the absence of albumin. Under the latter condition mitochondrial oxidation was severely depressed. In homogenates from normal liver peroxisomal oxidation was lower than mitochondrial oxidation at all ratios tested except when albumin was absent. In contrast with mitochondrial oxidation, peroxisomal oxidation did not produce ketones, was cyanide-insensitive, was not dependent on carnitine, and was not inhibited by (+)-octanoylcarnitine, malonyl-CoA and 4-pentenoate. Mitochondrial oxidation was inhibited by CoASH concentrations that were optimal for peroxisomal oxidation. In the presence of albumin, peroxisomal oxidation was stimulated by Triton X-100 but unaffected by freeze-thawing; both treatments suppressed mitochondrial oxidation. Clofibrate treatment increased mitochondrial and peroxisomal oxidation 2- and 6- to 8-fold, respectively. Peroxisomal oxidation remained unchanged in starvation and diabetes. Fatty acid oxidation was severely depressed by cyanide and (+)-octanoylcarnitine in hepatocytes from normal rats. Hepatocytes from clofibrate-treated rats, which displayed a 3- to 4-fold increase in fatty acid oxidation, were less inhibited by (+)-octanoylcarnitine. Hydrogen peroxide production was severalfold higher in hepatocytes from treated animals oxidizing fatty acids than in control hepatocytes. Assuming that all H2O2 produced during fatty acid oxidation was due to peroxisomal oxidation, it was calculated that the contribution of the peroxisomes to fatty acid oxidation was less than 10% both in cells from control and clofibrate-treated animals.
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PMID:Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats. 43 7

An "endoneurial" preparation from a rabbit tibial nerve fascicle was used to study the ability of peripheral nerve axons and Schwann cells to derive their composite energy requirements from glucose, D-beta-hydroxybutyrate, or albumin-bound palmitate, and the effects of insulin in vitro on their composite glucose utilization. Samples incubated with 5 mM glucose for 2 h maintained a stable O2 uptake and P-creatine and ATP concentrations, and they exhibited a slight increase in P-creatine/creatine ratio (the electron microscopic appearance of the preparation was previously shown to be unaltered under these conditions). The rate of glucose oxidation required to account for the O2 uptake accounted for 61% of the glucose uptake. In samples incubated without substrate for 2 h, a marked fall in tissue glucose was associated with a 50% decrease in O2 uptake and with decreases in P-creatine, ATP, and in the P-creatine/creating ratio. In medium lacking glucose but containing 5 mM DL-beta-hydroxybutyrate, a stable rate of D-beta-hydroxybutyrate uptake was observed, and acetoacetate production accounted for only a small fraction; significant decreases in O2 uptake or ATP were prevented, and, although P-creatinde and the P-creatine/creatine ratio fell, they remained significantly higher than after incubation without substrate. An efficient blood-nerve barrier to albumin is known to exist. Medium containing albumin-bound palmitate with molar ratios or palmitate/albumin of 1 or 2 (highest FFA concentration, 1.32 meq/L) failed to prevent decreases in P-creatine, ATP, and in the P-creatine/creatine ratio during incubations without glucose; the associated O2 uptakes suggested that the tissue is susceptible to respiratory uncoupling and depression son exposure to albumin-blund palmitate as compared with non-neural tissue. Insulin (100 or 1000 microU/ml) had no detectable effects on glucose utilization in the endoneurial preparation during 2-h incubations with 5 mM glucose or (U-14C) glucose. In contrast, in epineurial tissue from rabbit sciatic nerve, insulin (100 micronU/ml) increased (U-14C) glucose incorporation into CO2 and total lipid. The neural components of peripheral nerve are probably dependent on glucose as their major substrate for energy production and respiration under most physiologic conditions in which elevated plasma ketone body concentrations are absent; their composite glucose utilization is not subject to acute, direct regulation by insulin in concentrations that might reasonably be derived from plasma insulin of pancreatic origin.
Diabetes 1979 Oct
PMID:In vitro studies of the substrates for energy production and the effects of insulin on glucose utilization in the neural components of peripheral nerve. 47 82


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