Diadenosine polyphosphates are a group of low-weight compounds that increase after exposure to a wide variety of oxidants and have been suggested to act as "alarmones," alerting the cell to the onset of metabolic stress. We demonstrate here that glucose at concentrations that induce insulin release produce a 30- to 70-fold increase in the concentration of diadenosine triphosphate (Ap3A) and tetraphosphate (Ap4A) in beta-cells. Furthermore, Ap3A and Ap4A, at the concentrations found in glucose-stimulated cells, are effective inhibitors of the ATP-regulated K+ channels when applied to the intracellular side of excised membrane patches from cultured beta-cells. We suggest that Ap3A and Ap4A act as second messengers mediating a glucose-induced blockade of the pancreatic beta-cell ATP-regulated potassium channel.

Autonomic activation mediates the majority of the increase of glucagon secretion during insulin-induced hypoglycemia in several species including dogs, mice, and rats. However, the role of the autonomic nervous system to increase glucagon during hypoglycemia in humans remains controversial, and investigations in nonhuman primates have not been previously conducted. The autonomic contribution to glucagon secretion during hypoglycemia in a nonhuman primate was examined by two independent pharmacological approaches. Glucagon responses to clamped insulin-induced hypoglycemia were compared in conscious rhesus monkeys in the presence or absence of ganglionic blockade with trimethaphan, or during combined muscarinic and adrenergic receptor blockade with atropine, propranolol, and tolazoline. Insulin-induced hypoglycemia (plasma glucose = 1.9 +/- 0.1 mmol/l) activated parasympathetic nerves to the pancreas as assessed by increased plasma pancreatic polypeptide (PP) levels (delta = 135.0 +/- 36.8 pmol/l, P < 0.01), produced sympathoadrenal activation as assessed by elevations of plasma epinephrine (EPI) (delta = 22.3 +/- 2.95 nmol/l, P < 0.0005) and norepinephrine (NE) (delta = 3.72 +/- 0.77 mmol/l, P < 0.0025) and increased plasma immunoreactive glucagon (IRG) (delta = 920 +/- 294 ng/l, P < 0.025). Nicotinic ganglionic blockade with trimethaphan prevented parasympathetic (deltaPP = 16.5 +/- 16.3 pmol/l, P < 0.01 vs. control) and sympathoadrenal (deltaEPI = 1.52 +/- 0.98 nmol/l; deltaNE = -0.62 +/- 0.24 mmol/l, both P < 0.0025 vs. control) activation during hypoglycemia and inhibited the IRG response by 70% (delta = 278 +/- 67 ng/l, P < 0.025 vs. control). Combined muscarinic and adrenergic receptor blockade reduced parasympathetic activation (deltaPP = 48.3 +/- 16.3 pmol/l, P < 0.01 vs. control) and inhibited the IRG response by a similar degree to ganglionic blockade (deltaIRG = 284 +/- 60 ng/l, P < 0.025 vs. control). These results demonstrate by two independent pharmacological approaches that autonomic activation makes a substantial contribution to increased glucagon secretion during hypoglycemia of approximately 2.0 mmol/l in a species of nonhuman primate.

Insulin rapidly stimulates glucose transport in muscle fiber. This process controls the utilization of glucose in skeletal muscle, and it is deficient in various insulin-resistant states, such as non-insulin-dependent diabetes mellitus. The effect of insulin on muscle glucose transport is mainly due to the recruitment of GLUT4 glucose carriers to the cell surface of the muscle fiber. There is increasing evidence that the recruitment of GLUT4 carriers triggered by insulin affects selective domains of sarcolemma and transverse tubules. In contrast, GLUT1 is located mainly in sarcolemma and is absent in transverse tubules, and insulin does not alter its cellular distribution in muscle fiber. The differential distribution of GLUT1 and GLUT4 in the cell surface raises new questions regarding the precise endocytic and exocytic pathways that are functional in the muscle fiber. The current view of insulin-induced GLUT4 translocation is based mainly on studies performed in adipocytes. These studies have proposed the existence of intracellular compartments of GLUT4 that respond to insulin in a highly homogeneous manner. However, studies performed in skeletal muscle have identified insulin-sensitive as well as insulin-insensitive intracellular GLUT4-containing membranes. These data open a new perspective on the dynamics of intracellular GLUT4 compartments in insulin-sensitive cells.

Chronic activation of the sympathetic nervous system may be a pathogenetic mechanism by which hyperinsulinemia induces cardiovascular damage in insulin-resistant NIDDM patients. The influence of physiological hyperinsulinemia (approximately 700 pmol/l) on basal and stimulated sympathetic outflow was studied in 12 lean normotensive subjects with well-controlled NIDDM without complications and in 13 matched control subjects. Forearm blood flow (FBF) was measured with forearm plethysmography; sympathetic nervous system activity was assessed by the [3H]norepinephrine (NE) tracer method. NIDDM patients were insulin resistant (glucose infusion rates 31.8 +/- 3.8 vs. 48.7 +/- 2.0 mumol.kg-1.min-1 in control subjects, P < 0.01). After a mixed meal, NIDDM patients showed a hyperinsulinemic response (2-h insulin levels: NIDDM patients 324 +/- 34 pmol/l, control subjects 165 +/- 19 pmol/l, P < 0.001). Insulin infusion induced a vasodilator response (not significantly different between the groups). Arterial plasma NE levels and total-body NE spillover increased significantly (total spillover in NIDDM patients from 0.77 +/- 0.09 to 1.18 +/- 0.16 nmol.m-2.min-1, in control subjects from 0.98 +/- 0.14 to 1.23 +/- 0.18 nmol.m-2.min-1, P < 0.01 for all, not different between groups). Total-body NE clearance did not change. Sympathetic stimulation (lower-body negative pressure [LBNP] 15 mmHg) induced forearm vasoconstriction and increased arterial and venous plasma NE and total NE spillover. Responses of FBF and NE kinetics to LBNP were not significantly different between groups and were not altered by hyperinsulinemia. Although these nonobese subjects with uncomplicated NIDDM showed postprandial hyperinsulinemia and resistance to the effect of insulin on glucose metabolism, this group was not resistant to the vasodilator and sympathetic stimulant effects of insulin. Responses to sympathetic stimuli (LBNP) were normal and unaffected by physiological hyperinsulinemia. Therefore, because of daily life hyperinsulinemia, chronic sympathetic stimulation could be operative in these patients and may explain the increased incidence of hypertension and/or cardiovascular complications.

Levels of lipoprotein(a) [Lp(a)], apolipoprotein (apo) B, and lipoprotein cholesterol distribution using density-gradient ultracentrifugation were measured as part of a cross-sectional study at the final follow-up examination (mean 6.2 years) in the Diabetes Control and Complications Trial. Compared with the subjects in the conventionally treated group (n = 680), those subjects receiving intensive diabetes therapy (n = 667) had a lower level of Lp(a) (Caucasian subjects only, median 10.7 vs 12.5 mg/dl, respectively; P = 0.03), lower apo B (mean 83 vs. 86 mg/dl, respectively; P = 0.01), and a more favorable distribution of cholesterol in the lipoprotein fractions as measured by density-gradient ultracentrifugation with less cholesterol in the very-low-density lipoprotein and the dense low-density lipoprotein fractions and greater cholesterol content of the more buoyant low-density lipoprotein. Compared with a nondiabetic Caucasian control group (n = 2,158), Lp(a) levels were not different in the intensive treatment group (median 9.6 vs. 10.7 mg/dl, respectively; NS) and higher in the conventional treatment group (9.6 vs. 12.5 mg/dl, respectively; P < 0.01). No effect of renal dysfunction as measured by increasing albuminuria or reduced creatinine clearance on Lp(a) levels could be demonstrated in the diabetic subjects. Prospective follow-up of these subjects will determine whether these favorable lipoprotein differences in the intensive treatment group persist and whether they influence the onset of atherosclerosis in insulin-dependent diabetes.

In patients with insulin-dependent diabetes mellitus (IDDM), microalbuminuria is a predictor of widespread severe microangiopathy and macroangiopathy. Patients with microalbuminuria show generalized dysfunction of the vascular endothelium, but it is unknown whether endothelial dysfunction precedes the development of microalbuminuria. We examined a cohort of 17 IDDM patients at baseline and on three occasions during a follow-up of (median) 64 months (range 51-89). All had normal (< 15 micrograms/min) urinary albumin excretion (UAE) at the first three examinations. At the fourth examination, 11 patients had normal UAE and 6 had microalbuminuria (median 25.7 micrograms/min [range 15.3-42.8]). Compared with patients with normal UAE, microalbuminuric patients had significantly higher plasma levels of von Willebrand factor (vWF), a marker of endothelial dysfunction, at the second (200% [168-274] vs. 131% [69-186]), third (208% [188-270] vs. 125% [82-190]), and fourth examinations (231% [202-269] vs. 132% [88-208], P < 0.0001), but not at baseline (128% [98-161] vs. 122% [87-210]). An increase in vWF preceded the occurrence of microalbuminuria by approximately 3 years. The groups did not differ with regard to age, diabetes duration, blood pressure, mean glycated hemoglobin and cholesterol, smoking habits, or extent of retinopathy. Endothelial dysfunction, as estimated by plasma vWF concentration, precedes and may predict the development of microalbuminuria in IDDM.

Sulfonylurea drugs are widely used in the therapy of NIDDM. The improvement of glucose tolerance after long-term treatment of NIDDM patients with the drug can be explained by stimulation of glucose utilization in peripheral tissues that are characterized by insulin resistance in these patients. We studied whether the novel sulfonylurea drug, glimepiride, stimulates glucose transport into isolated insulin-resistant rat adipocytes. After long-term incubation of the cells in primary culture with high concentrations of glucose, glutamine, and insulin, stimulation of glucose transport by insulin was significantly reduced both with respect to maximal responsiveness (65% decrease of Vmax) and sensitivity (2.6-fold increase of ED50) compared with adipocytes cultured in medium containing a low concentration of glucose and no insulin. This reflects insulin resistance of glucose transport. In contrast, both responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only marginally reduced in insulin-resistant adipocytes (15% decrease of Vmax; 1.2-fold increase of ED50) versus control cells. Glimepiride, in combination with glucose and glutamine during the primary culture, caused desensitization of the glucose transport system toward stimulation by insulin, but to a lesser degree than insulin itself (50% reduction of Vmax; ninefold increase of ED50). Again, the maximal responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only slightly diminished. The presence of glimepiride during primary culture did not antagonize the induction of insulin resistance of glucose transport. The stimulation of glucose transport in insulin-resistant adipocytes by glimepiride is caused by translocation of glucose transporters from low-density microsomes to plasma membranes as demonstrated by subcellular fractionation and immunoblotting with anti-GLUT1 and anti-GLUT4 antibodies. Immunoprecipitation of GLUT4 from 32Pi- and [35S]methionine-labeled adipocytes revealed that the insulin resistance of GLUT4 translocation is accompanied by increased (three- to fourfold) phosphorylation of GLUT4 in both low-density microsomes and plasma membranes. Short-term treatment of desensitized adipocytes with glimepiride or insulin reduced GLUT4 phosphorylation by approximately 70 and 25%, respectively, in both fractions. We conclude that glimepiride activates glucose transport by stimulation of GLUT1 and GLUT4 translocation in rat adipocytes via interference at a site downstream of the putative molecular defect in the signaling cascade between the insulin receptor and the glucose transport system induced by high concentrations of glucose and insulin. The molecular site of glimepiride action is related to GLUT4 phosphorylation/dephosphorylation, which may regulate glucose transporter activity and translocation.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytoplasmic islet cell antibodies are well-established predictive markers of IDDM. Although target molecules of ICA have been suggested to be gangliosides, human monoclonal ICA of the immunoglobulin G class (MICA 1-6) produced from a patient with newly diagnosed IDDM recognized glutamate decarboxylase as a target antigen. Here we analyzed the possible heterogeneity of target antigens of ICA by subtracting the GAD-specific ICA staining from total ICA staining of sera. This was achieved 1) by preabsorption of ICA+ sera with recombinant GAD65 and/or GAD67 expressed in a baculovirus system and 2) by ICA analysis of sera on mouse pancreas, as GAD antibodies do not stain mouse islets in the immunofluorescence test. We show that 24 of 25 sera from newly diagnosed patients with IDDM recognize islet antigens besides GAD. In contrast, GAD was the only islet antigen recognized by ICA from 7 sera from patients with stiff man syndrome. Two of these sera, however, recognized antigens besides GAD in Purkinje cells. In patients with IDDM, non-GAD ICA were diverse. One group, found in 64% of the sera, stained human and mouse islets, whereas the other group of non-GAD ICA was human specific. Therefore, mouse islets distinguish two groups of non-GAD ICA and lack additional target epitopes of ICA besides GAD. Longitudinal analysis of 6 sera from nondiabetic ICA+ individuals revealed that mouse-reactive ICA may appear closer to clinical onset of IDDM in some individuals. Mouse-reactive ICAs, however, remained absent in 36% of the patients at diagnosis of IDDM.

Isolated ventral and dorsal rat spinal roots incubated in normal (2.5 mM) or high glucose (25 mM) concentrations or in high concentrations of other hexoses were exposed transiently to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials, extracellular direct current potentials, and interstitial pH were continuously recorded before, during, and after hypoxia. Ventral roots incubated in 25 mM D-glucose showed resistance to hypoxia. Dorsal roots, on the other hand, revealed electrophysiological damage by hyperglycemic hypoxia as indicated by a lack of posthypoxic recovery. In both types of spinal roots, interstitial acidification was most pronounced during hyperglycemic hypoxia. The changes in the sensitivity to hypoxia induced by high concentrations of D-glucose were imitated by high concentrations of D-mannose. In contrast, D-galactose, L-glucose, D-fructose, and L-fucose did not have such effects. Resistance to hypoxia, hypoxia-generated interstitial acidification, and hypoxia-induced electrophysiological damage were absent after pharmacological inhibition of nerve glycolysis with iodoacetate. These observations indicate 1) that enhanced anaerobic glycolysis produces resistance to hypoxia in hyperglycemic peripheral nerves and 2) that acidification may impair the function of peripheral axons when anaerobic glycolysis proceeds in a tissue with reduced buffering power.

We previously described a prosthetic group methodology for incorporating 18F into peptides and showed that 18F-labeled insulin (18F-insulin) binds to insulin receptors on human cells (IM-9 lymphoblastoid cells) with affinity equal to that of native insulin (1). We now report studies using 18F-insulin with positron emission tomography to study binding to insulin receptors in vivo. Positron emission tomography scans were performed in six rhesus monkeys injected with 0.3-1.4 mCi of 18F-insulin (approximately 0.1 nmol, SA 4-11 Ci/mumol). Integrity of the tracer in blood, determined by immunoprecipitation, was 94% of control for the first 5 min and decreased to 31% by 30 min. Specific, saturable uptake of 18F was observed in the liver and kidney. Coinjection of unlabeled insulin (200 U, approximately 1 nmol) with the 18F-insulin reduced liver and increased kidney uptake of the labeled insulin. Liver radioactivity was decreased by administration of unlabeled insulin at 3 min, but not 5 min, after administration of the tracer, while some kidney radioactivity could be displaced 5 min after injection. Clearance of 18F was predominantly in bile and urine. 18F-insulin is a suitable analogue for studying insulin receptor-ligand interactions in vivo, especially in the liver and kidney.

Glucose is reabsorbed from the glomerular filtrate in the proximal segment of the renal tubule in two stages. The first stage is uphill transport across the brush border membrane by Na(+)-glucose cotransport and the second stage is downhill transport across the basolateral membrane by facilitated diffusion. Genes for both a renal Na(+)-glucose cotransporter (SGLT1) and a renal facilitated glucose transporter (GLUT2) have been cloned and sequenced. To examine whether SGLT1 and GLUT2 colocalize to the same tubular epithelial cells in rat kidney, double-immunoperoxidase studies with dual chromogens and paraformaldehyde perfusion-fixed frozen sections of rat kidney were performed. Antipeptide antisera were prepared against rat GLUT2 (amino acids 510-522) and rabbit SGLT1 (amino acids 402-420). Proximal tubules were identified immunocytochemically with an antiserum raised against a synthetic peptide corresponding to the 21 amino acids at the COOH-terminal of the heavy chain of rat gamma-glutamyl transpeptidase, which is a proximal tubule-specific enzyme. The anti-GLUT2 antiserum strongly stained the basolateral membrane of 46% of cortical tubules, whereas the SGLT1 antiserum stained the brush border of 56% of the cortical tubules. The gamma-glutamyl transpeptidase antiserum also stained the brush border of 51% of the cortical tubules. GLUT2 and SGLT1 colocalized to 40% of cortical epithelium, but 16% of cortical epithelial cells were immunopositive for brush border SGLT1 and immunonegative for basolateral GLUT2. These gamma-glutamyl transpeptidase staining results suggest that at least 50% of the tubules in the cortex are proximal tubules and that SGLT1 and GLUT2 colocalize to most proximal tubules. The fact that SGLT1 antiserum immunoreacted with tubules unreactive to the GLUT2 antiserum suggests that either the SGLT1 epitope is conserved on a related brush border protein or that there is another GLUT transporter responsible for the exit of sugar from these proximal tubule cells.

Islet cell antibodies (ICAs) were determined in a large cohort of white nondiabetic schoolchildren (n = 4287) from a homogenous population in southern Germany. The prevalence of ICA levels greater than or equal to 5 Juvenile Diabetes Foundation (JDF) U was 1.05% (95% confidence interval 0.8-1.4%). Analysis of HLA-DR beta and -DQ beta alleles revealed that the specificities found to be increased in insulin-dependent (type I) diabetic subjects with the same ethnic background were also associated with ICA positivity in the nondiabetic schoolchildren. HLA-DR3 (P less than 0.01) and -DR4 (P less than 0.01) phenotypes and absence of Asp residue (P less than 0.01) at codon 57 of the HLA-DQ beta-chain were significantly increased in ICA+ compared with control subjects. High levels of ICAs, which were categorized as either greater than or equal to 17 or greater than or equal to 30 JDF U, were found to be associated with amino acids other than Asp at position 57 of the HLA-DQ beta-chain. No association of ICA level was found for HLA-DR phenotypes.

To determine the role of the autonomic nervous system (ANS) in mediating the glucagon response to marked insulin-induced hypoglycemia in dogs, we measured arterial and pancreatic venous glucagon responses to insulin-induced hypoglycemia during acute, terminal experiments in halothane-anesthetized dogs in which the ANS was intact (control; n = 9), pharmacologically blocked by the nicotinic ganglionic antagonist hexamethonium (n = 6), or surgically ablated by cervical vagotomy and cervical spinal cord section (n = 6). In control dogs, insulin injection caused plasma glucose to fall by 4.4 +/- 0.2 mM to a nadir of 1.7 +/- 0.2 mM. Arterial epinephrine (EPI) levels increased by 13,980 +/- 1860 pM (P less than 0.005), confirming marked activation of the ANS. Pancreatic output of glucagon increased from 0.53 +/- 0.12 to 2.04 +/- 0.38 ng/min during hypoglycemia (change [delta] +1.51 +/- 0.33 ng/min, P less than 0.005). This increased arterial plasma glucagon from 27 +/- 3 to 80 +/- 15 ng/L (delta +52 +/- 14 ng/L, P less than 0.025). Hexamethonium markedly reduced the ANS response to insulin injection (delta EPI +2130 +/- 600 pM, P less than 0.025 vs. control) despite a similar fall of plasma glucose (delta -4.1 +/- 0.2 mM) and a lower nadir (0.6 +/- 0.1 mM). Both the pancreatic glucagon response (delta glucagon output +0.45 +/- 0.2 ng/min) and the arterial immunoreactive glucagon response (delta +5 +/- 4 ng/L) were substantially reduced by hexamethonium (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

In primary culture of adult rat hepatocytes, vanadate in the presence of glucose stimulates the expression of the liver (L-type) pyruvate kinase gene. Glucose by itself was inactive, and vanadate, like insulin, was also inefficient in the absence of glucose. Similar results were obtained on glucokinase gene expression. An analogue of cAMP, 8-(4-chlorophenylthio)-cAMP, inhibited the production of L-type pyruvate kinase and glucokinase mRNAs in the presence of glucose plus vanadate.

From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.

Because successful human islet transplantation requires large quantities of viable islets that must be separated from the highly immunogenic exocrine tissue and because handpicking is too time-consuming and laborious to be clinically relevant, a new approach for solving this problem has been established in rat models. It is based on the principle that magnetic microspheres (MMSs) coupled to lectins with binding specificity for the exocrine tissue portion are trapped in an electromagnetic field, thus providing effluent islets of a high degree of purity. In this study our aim was to adapt this principle to human islet preparations. In this context our prime interest was focused on a lectin suitable for human pancreatic tissue. Of 19 different lectins tested, only 1, Wisteria floribunda agglutinin (WFA), is suitable, as shown by immunofluorescence, MMS-lectin binding, and magnetic separation.

An immunogold-silver enhancement technique, which combines effective labeling of viable isolated islets with the ultrastructural resolution of cytological details, was applied in electron microscopy to identify major histocompatibility complex (MHC) structures on islet cells. Incubation of freshly isolated islets from CAP (RT1c) and LEW (RT1l) rats with OX18, an MHC class I antibody, showed strong positive reactivity in macrophages and/or dendritic-like cells (M0-DCs) and vascular endothelial cells (VEs) and a comparatively weaker reactivity in endocrine alpha-, beta-, and delta-cells. With MHC class II antibody OX6 (anti-I-A), M0-DCs were strongly labeled in both rat strains on the surface and on internal structures. Three of five particularly high titered batches of OX6 revealed MHC class II expression on VE and beta-cells. Four days of in vitro culture in combination with a high concentration of glucose and interferon-gamma induced strong enhancement of MHC class I structures and, to a lesser extent, class II structures on beta-cells.

Total immunoreactive insulin (IRI) is conventionally determined by radioimmunoassays. IRI measurement in rats can be made more sensitive, accurate, and practical, as demonstrated by a new modified enzyme-linked immunosorbent assay (ELISA). It is characterized by indirect binding of an anti-insulin antibody by an antiglobulin antibody and uses the principle of competitive saturation. In this ELISA, IRI can be determined in a wide range of concentrations, corresponding to the standards. The standard curve ranges from 100 to 0.049 ng/ml IRI (1 ng/ml approximately 23.4 microU/ml approximately 172 pM rat insulin). The statistical analysis shows between- and within-assay coefficients of variation of less than or equal to 15%.

Specific and total activities of the disaccharidases, sucrase, maltase, and lactase are increased in mucosa of the small intestine of the streptozotocin diabetic rat. Because disaccharidases are essential for terminal digestion of carbohydrate, and disaccharidase deficiency is a common clinical problem, understanding the mechanisms regulating disaccharidase activity is important. In normal animals, disaccharidase activities are determined by route of feeding and are decreased by parenteral feeding. The indirect exocrine, endocrine, neurocrine, and paracrine functions of the gastrointestinal tract that are dependent on feeding via the gut are greatly decreased in parenteral as compared with enteral feeding. Hormone secretion by the gut and the pattern of response after feeding may be abnormal in diabetes and might be regulatory for disaccharidases. We tested the hypothesis that the elevated intestinal disaccharidases in diabetes are dependent on enteral feeding. Streptozotocin-injected rats (diabetics) and vehicle-injected rats (controls) were fed rat chow ad libitum for 4 days. A subset of control and diabetic animals was then killed to determine disaccharidase activity of the jejunum at the start of pair-feeding the elemental diet. The remaining animals were fed 60 cal/day of glucose, amino acid (Travasol), and electrolyte solution either intragastrically or intravenously for 4 days. Specific and total activities of disaccharidases were greater in diabetics than in controls under all feeding conditions. In controls, the pattern of activity of disaccharidase specific activity was initial greater than intragastric greater than intravenous. In diabetics, disaccharidase specific activities did not differ among groups. In both controls and diabetics, mean mucosal mass was highest initially; intermediate with intragastric feeding; and lowest with intravenous feeding. In both controls and diabetics, total disaccharidases decreased from initial to intragastric to intravenous. We conclude: (1) disaccharidase specific activity in controls is sensitive to feeding route and nature of diet, but is nearly independent of these factors in diabetics; (2) total disaccharidase activities respond to feeding stimuli in parallel with changes in mucosal mass in both controls and diabetics; and (3) the lack of feeding effect on the elevated specific activities of disaccharidases in diabetes suggests that this elevation is a response to the diabetic state and is independent of enteral factors such as luminal nutrition and gastrointestinal hormones.