Normoglycemic Period Research Articles

Fabrication of Tip-Hollow and Tip-Dissolvable Microneedle Arrays for Transdermal Drug Delivery.

We developed a modified micromolding method for the mass production of a novel tip-hollow microneedle array (MA). The tip-hollow MA was fabricated by tuning of the vacuum degree at -80 kPa for 60 s during the micromolding process. Subsequently, a tip-dissolvable MA encapsulated with drugs in the microcraters was fabricated from tip-hollow MA using repeated dipping and the freeze-drying process. Both the tip-hollow and tip-dissolvable MAs could easily penetrate in the rabbit skin without breakage, while the tip-hollow MA can just create a shallow loop hole in the skin. The drug-loaded tip-dissolvable MA can rapidly dissolve, releasing and diffusing the drug in the skin. The tip-dissolvable MA exhibited the best drug permeation ability in that the corresponding flux through the punctured skin using tip-dissolvable MA loaded with Rhodamine B is about 1.7- and 5.8-fold of that through the punctured skin using solid MA and the intact skin, respectively. The tip-dissolvable MA loaded with 5 IU insulin was fabricated to in vivo treat the type 1 diabetic SD rats. The tip-dissolvable MA had a good hypoglycemic effect and exhibited longer normoglycemic period in comparison with subcutaneous injection (5 IU). Therefore, our tip-dissolve MA is a promising medical device for transdermal drug delivery.

Persistent Diuresis Associated Dapagliflozin Treatment

Diabetic ketoacidosis is a clinical entity characterized by high blood sugar, ketone positivity and high anion gap metabolic acidosis. In these patients; polyuria is commonly detected due to hyperglycemia. Polyuria-induced dehydration may even be seen, especially in elderly patients. Polyuria is not expected to continue after hyperglycemia has resolved. We reported in this article; a 55 years old man with type-2 diabetes mellitus who was treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (dapagliflozin) who developed diabetic ketoacidosis and persistent diuresis in the post-treatment normoglycemic period.

Dynamic estimation of cardiac repolarization characteristics during hypoglycemia in healthy and diabetic subjects

Hypoglycemia is known to affect the repolarization characteristics of the heart, but the mechanisms behind these changes are not completely understood. We analyzed repolarization characteristics continuously from 22 subjects during normoglycemic period, transition period (blood glucose concentration decreasing) and hypoglycemic period from nine healthy controls (Healthy), six otherwise healthy type 1 diabetics (T1DM) and seven type 1 diabetics with disease complications (T1DMc). An advanced principal component regression (PCR)-based method was used for estimating ECG parameters beat-by-beat, and thus, continuous comparison between the repolarization characteristics and blood glucose values was made. We observed that hypoglycemia related ECG changes in the T1DMc group were smaller than changes in the Healthy and T1DM groups. We also noticed that when glucose concentration remained at a low level, the heart rate corrected QT interval prolonged progressively. Finally, a few minutes time lag was observed between the start of hypoglycemia and cardiac repolarization changes. One explanation for these observations could be that hypoglycemia related hormonal changes have a significant role behind the repolarization changes. This could explain at least the observed time lag (hormonal changes are slow) and the lower repolarization changes in the T1DMc group (hormonal secretion lowered in long duration diabetics).

Cryopreserved Agarose-Encapsulated Islets As Bioartificial Pancreas: A Feasibility Study

A bioartificial pancreas in which islets of Langerhans (islets) are encapsulated within a semipermeable membrane, such as agarose, has been proposed for treating type I diabetic mellitus. However, the long-term storage for providing a convenient and easily accessible supply still remains an issue. We investigated cryopreservation as a potential method of long-term storage for agarose-encapsulated islets (Mic-islets). The morphology, insulin secretion, and histochemical staining of cryopreserved Mic-islets were analyzed. Streptozotocin-induced diabetic mice were transplanted intraperitoneally with 1000, 2000, and 3000 Mic-islets after cryopreservation in KYO-1 vitrification solution. Blood glucose levels were measured and immunohistochemical analyses were performed at 41 days posttransplantation. Transplanted cryopreserved Mic-islets restored normoglycemia in diabetic mice. The mean (+/-SD) normoglycemic periods were 32.0+/-13.2 days and 46.3+/-13.3 days for recipients of 1000 (n=5) and 2000 (n=4) cryopreserved Mic-islets, respectively, whereas the mean normoglycemic period was 53.2+/-16.7 days for recipients of 1000 noncryopreserved Mic-islets (n=7). These data indicate that cryopreserved Mic-islets transplanted as a bioartificial pancreas successfully controlled blood glucose levels for extended periods. Cryopreserved agarose-encapsulated islets could successfully control the blood glucose level for a long period as a bioartificial pancreas.

Blood Pressure Early in Diabetes Depends on a Balance Between Glomerular Filtration Rate and the Renin-Angiotensin System

Onset of diabetes increases plasma renin activity (PRA) and glomerular filtration rate (GFR), but blood pressure (BP) is normal. In this study, a 70% surgical reduction in kidney mass (RK) was used to decrease baseline GFR and to prevent hyperfiltration during diabetes, and angiotensin converting enzyme inhibitors (ACEI) were used to inhibit angiotensin II (AngII) production, to test the hypothesis that a balance between GFR and AngII is required for normal BP early in diabetes. Diabetes was induced with streptozotocin (STZ) (35 mg/kg intravenously); and after 7 days of hyperglycemia (range: 408 to 486 mg/dL), insulin was intravenously infused continuously for a 4-day normoglycemic recovery period. In normal kidney (NK) rats, diabetes increased PRA (2.4 +/- 0.6 to 4.6 +/- 0.5 ngAI/mL/h) and GFR (2.9 +/- 0.1 to 3.5 +/- 0.2 mL/min), and there was no change in mean arterial pressure (MAP) (89 +/- 1 v 91 +/- 1 mm Hg, measured 18 h/day). There was no change in either GFR or AngII during diabetes in RK+ACEI rats, and their MAP also did not change. Thus, the maintenance of normal MAP was accompanied by a balance between GFR and AngII in both of those groups. In NK+ACEI rats, however, GFR increased significantly with no change in AngII, and MAP decreased significantly during diabetes by approximately 8 mm Hg. In RK rats, PRA increased (0.5 +/- 0.1 to 2.6 +/- 0.5) but GFR did not increase, and MAP increased significantly by approximately 16 mm Hg. All rats were in sodium balance by day 4 of diabetes. These data support the hypothesis that normotension early in diabetes requires a balance between the increased AngII and GFR, and that BP will increase if AngII increases but GFR does not.

Long-Term Normoglycemia in Rats Receiving Transplants with Encapsulated Islets

To follow up on previously successful transplantation of encapsulated islets in mice, the present study was performed in rats to determine the effects of several factors, including alginate composition and concentration of cross-linking agent and capsule size on the effectiveness of encapsulated islets. Highly purified alginate of either high guluronic acid or high mannuronic acid (M) with low endotoxin content was used. Regular-size (0.8-1.1 mm) or small microcapsules (0.5-0.7 mm) were produced by cross-linking with BaCl2 without additional poly-L-lysine coating and were transplanted into abdominal cavity of normoglycemic (empty capsules) or streptozotocin induced diabetic Lewis rats (islet containing capsules). Empty regular-size capsules made of different alginate compositions had similar biocompatibility and stability results. Compared with empty capsules, regular-size capsules made of high-M alginate containing syngeneic islets had inferior stability indicated with lower fractional volume retrieved. Islet-containing smaller-size microcapsules made of high-M alginate were more stable and had less cellular attachment compared with the regular-size capsules, although the normoglycemic period was comparable between two groups of rats receiving transplants with smaller-size microcapsules (48+/-8 days, n=8) or regular-size capsules (59+/-11 days, n=4) in allogeneic experiments. In syngeneic experiments, all of the rats (n=4) maintained normoglycemia up to 210 days after transplantation. These results indicate that regular-size alginate capsules do less well in rats than in our previous experiments with mice. Smaller capsules made of alginate cross-linked with barium appear to provide better stability and may be a useful strategy for use in larger recipients.

Prolongation of the normoglycemic period in animals with acute experimental diabetes by means of various types of tissue transplantation.

Prolongation of the normoglycemic period in animals with acute experimental diabetes by means of various types of tissue transplantation.

The rescue effect of 15-deoxyspergualin on intraperitoneal microencapsulated xenoislets.

Because the development of surface neogrowth composed mainly of macrophages and fibroblasts precedes the recurrence of hyperglycemia in treated diabetic animals, the pericapsular macrophages may adversely affect the graft function of i.p. alginate-poly-L-lysine-alginate (A-P-A) microencapsulated islets. In order to clarify the role of pericapsular macrophages on late islet xenograft dysfunction, we investigated whether 15-deoxyspergualin (15-DSG), a macrophage inhibitor, has a rescue effect on the recurrent hyperglycemia in streptozotocin-induced diabetic mice that had been treated with i.p. transplantation of A-P-A microencapsulated rat islets. The mean duration of normoglycemia (whole blood glucose level below 8.3 mmol/l) in streptozotocin-induced diabetic mice treated with implantation of about 2200-2400 of A-P-A microencapsulated rat islets was 75 days. When the blood glucose levels were higher than 11.1 mmol/l for two consecutive determinations, 15-DSG at a dose of 0.625 mg/kg body weight or isotonic sodium chloride solution (control group) was given daily s.c.. The blood glucose levels decreased significantly from 13.9 +/- 0.5 mmol/l to 11.0 +/- 1.3 mmol/l (n = 18, p < 0.05) at the fourth day and to 7.6 +/- 1.0 mmol/l (n = 18) at the 14th day of 15-DSG administration. That was not significantly different from the mean glycemic level during the normoglycemic period (7.6 +/- 1.0 vs. 7.0 +/- 1.7 mmol/l, n = 18, p = NS). Isotonic sodium chloride solution injections did not reduce glycemic levels of mice in the control group. As another control, 10 streptozotocin-induced diabetic mice were given the same daily doses of 15-DSG for 14 days. 15-DSG did not decrease the blood glucose levels of diabetic mice in the control group. We further studied the effect of 15-DSG on the expression of interleukin-1beta (IL-1beta) in peritoneal exudate mononuclear cells (PEMCs) using reverse transcription-polymerase chain reaction. It was found that the mRNA of IL-1beta was undetectable in PEMCs of 15-DSG-treated diabetic mice even after those cells were stimulated by lipopolysaccharides in vitro. Administration of 15-DSG at a daily dose of 0.625 mg/kg body weight from the 22nd to the 28th day after transplantation and 7 consecutive days every 3 weeks thereafter did not prolong graft survival of i.p. microencapsulated rat islets. Our data suggest that 15-DSG has a rescue effect when A-P-A microencapsulated islets have induced cellular overgrowth that threatens the survival of the graft. It is possible that the surface overgrowth composed of macrophages is involved in the pathophysiology of late failure of A-P-A microencapsulated xenogeneic islets.

Successful islet auto- and allotransplantation in diabetic pigs.

Because of its anatomical and physiological similarities to humans, the pig appears to be a suitable large animal model for preclinical studies of islet transplantation. The aim of this study was to investigate islet auto- and allotransplantation in a pig model with diabetes induced by total pancreatectomy. Porcine islets were isolated by a continuous digestion-filtration device at 32 degrees C and purified by a discontinuous iso-osmolar Ficoll-sodium-diatrizoate gradient on a Cobe 2991. The purified islets were autografted into the liver or the renal subcapsular space. The liver appears to be a more suitable site for the islet grafts than the renal subcapsular space, and the minimal amount of islets for reversal of diabetes is >5 microl/kg of body weight. Persistent normoglycemia (fasting blood glucose level: 72.4+/-44.38 mg/dl) with a normal insulin secretion response to glucose stimulation was successfully achieved in five of six diabetic pigs by implanting a sufficient islet mass into the liver. Triple-drug immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone did not prevent porcine islet allografts from experiencing early failure. However, the addition of 15-deoxyspergualin to the triple-drug immunosuppressive regimen significantly prolonged the function of the islet allografts. When antithymocyte globulin was added to the above-mentioned immunosuppressive drug regimen, the normoglycemic period was prolonged to more than 1 month (fasting blood glucose level: 75.4+/-17 mg/dl). We conclude that autotransplantation with a sufficient islet mass can induce normoglycemia with a normal insulin secretion response to glucose stimulation in pancreatectomized diabetic pigs and that allotransplantation can be successfully achieved when 15-deoxyspergualin and antithymocyte globulin are combined with the triple-drug immunosuppression described above. However, this immunosuppressive protocol results in a high rate of infectious complications.

Prolonged effect of troglitazone (CS-045) on xenograft survival of hybrid artificial pancreas

Troglitazone (CS-045), a thiazolidinedione derivative, is a new oral antidiabetic agent that enhances insulin sensitivity and improves insulin responsiveness. In this study we examined the effects of CS-045 on the survival of xenografted bioartificial pancreas. Isolated rat islets were microencapsulated with three-layer agarose microcapsules (polybrene, carboxymethyl cellulose, and an agarose-polystyrene sulfonic acid mixture). Diabetes was induced by intraperitoneal injection of streptozotocin 220 mg/kg. Recipient diabetic mice were separated into two groups. In the CS-045 treated group, the recipient mice were given feed mixed with CS-045 (0.2% w/w) starting from 1 wk before transplantation up to graft failure. The mice in the control group had feed without CS-045. Three hundred microencapsulated rat islets were xenotransplanted into the intraperitoneal cavity of each recipient mouse in both groups. One month after xenotransplantation, IVGTT was performed for all recipients. Xenotransplantation of 300 rat islets in microcapsules decreased the nonfasting blood glucose levels of both groups within 2 days. In the CS-045-treated group ( n = 3), the normoglycemic period lasted for more than 1 mo without administration of immunosuppressive drugs (45 ± 4.3 days). However, in the control group ( n = 4), the blood glucose levels of all recipients were already elevated on day 4. In the IVGTT study, the glucose assimilation was markedly and significantly better in the CS-045-treated group than in the control group (K = 1.7 ± 0.1 vs. 0.7 ± 0.28 respectively, p < 0.01). This study demonstrates that a newly developed oral antidiabetic agent, CS-045 could favorably ameliorate the diabetic state of the recipients xenotransplanted with the bioartificial pancreas, leading to an improved glucose tolerance and longer xenograft survival.

Prolonged effect of troglitazone (CS-045) on xenograft survival of hybrid artificial pancreas.

Troglitazone (CS-045), a thiazolidinedione derivative, is a new oral antidiabetic agent that enhances insulin sensitivity and improves insulin responsiveness. In this study we examined the effects of CS-045 on the survival of xenografted bioartificial pancreas. Isolated rat islets were microencapsulated with three-layer agarose microcapsules (polybrene, carboxymethyl cellulose, and an agarose-polystyrene sulfonic acid mixture). Diabetes was induced by intraperitoneal injection of streptozotocin 220 mg/kg. Recipient diabetic mice were separated into two groups. In the CS-045 treated group, the recipient mice were given feed mixed with CS-045 (0.2% w/w) starting from 1 wk before transplantation up to graft failure. The mice in the control group had feed without CS-045. Three hundred microencapsulated rat islets were xenotransplanted into the intraperitoneal cavity of each recipient mouse in both groups. One month after xenotransplantation, IVGTT was performed for all recipients. Xenotransplantation of 300 rat islets in microcapsules decreased the nonfasting blood glucose levels of both groups within 2 days. In the CS-045-treated group (n = 3), the normoglycemic period lasted for more than 1 mo without administration of immunosuppressive drugs (45 +/- 4.3 days). However, in the control group (n = 4), the blood glucose levels of all recipients were already elevated on day 4. In the IVGTT study, the glucose assimilation was markedly and significantly better in the CS-045-treated group than in the control group (K = 1.7 +/- 0.1 vs. 0.7 +/- 0.28 respectively, p < 0.01). This study demonstrates that a newly developed oral antidiabetic agent, CS-045 could favorably ameliorate the diabetic state of the recipients xenotransplanted with the bioartificial pancreas, leading to an improved glucose tolerance and longer xenograft survival.

Feasibility of agarose microbeads with xenogeneic islets as a bioartificial pancreas.

A bioartificial pancreas, that is, transplantation of islets of Langerhans (islets) which are enclosed in a semipermeable membrane, has been proposed as a treatment for type I diabetes. The islets are immuno-isolated from the host by the semipermeable membrane preventing rejection while maintaining control of glucose metabolism for an extended period. The purpose of the current research is to evaluate the feasibility of preparing agarose microbeads with xenogeneic hamster islets as a bioartificial pancreas in streptozotocin induced diabetic mice. In the recipients with a low level of anti-hamster antibodies, the combination of encapsulation of hamster islets in 5% agarose microbeads and in vitro culture of them prolonged xenograft survivals. Four of 6 recipients were still normoglycemic at 100 days after implantation. However, the same procedure was not effective in the recipients which were sensitized in advance by transplantation of free hamster islets and thus had high levels of anti-hamster antibodies. The average normoglycemic period was 32 days. Antibodies permeated through the microbeads and activated complement on the cell surfaces. The network of agarose microbeads was rendered dense by increasing the concentration of agarose to restrict the diffusion of antibodies. Graft survivals were prolonged with increasing concentrations of agarose. As an analysis using diffusion equations predicted, the survivals were inversely proportional to the diffusion coefficient of IgG in each agarose gel. Islet xenotransplantation was enabled by the combination of the microbeads with a concentration of agarose higher than 7.5% and in vitro culture even in recipients having a high level of preformed antibodies.

A diabetic rabbit model for pig islet xenotransplantation.

An alloxan-diabetic rabbit model was established for the testing of the function of discordant xenogeneic pig islets isolated and purified from adult pig pancreata. The functional state of the pig islet transplants and immunological state of the rabbit recipients were assessed. Intraportal transplantation of 0.47 +/- 0.01 ml of pig islets with estimated 57418 +/- 5020 in number containing an estimated insulin content of 33.93 +/- 2.97 units (n = 7; mean +/- SEM) resulted in the normalization of blood glucose with a corresponding rise in insulin levels in the diabetic rabbit recipients for 2 days. An intravenous glucose tolerance test performed in 4 recipients during the normoglycemic period resulted in an improved K rate (2.5 +/- 0.4) over the diabetic controls, but this was significantly lower than the normal control animals (K rate = 4.5 +/- 0.4; n = 8). In vitro studies demonstrated that the preformed antibodies detected in the rabbit recipients were cytotoxic to the pig islet cells and lymphocytes. Heat treatment at 56 degrees C and mercaptoethanol treatment markedly reduced the cytotoxic activities of the sera. These findings implicated involvement of complement and IgM class antibodies in the killing of the pig islet cells. Furthermore, pig islet transplants at the kidney capsule site were coated with IgM class antibodies. This study has demonstrated that pig islets can be successfully isolated and purified in sufficient numbers for xenotransplantation studies in alloxan-diabetic rabbit. The porcine islet-to-alloxan diabetic rabbit combination can serve as a highly stringent and useful discordant model for assessing the effectiveness of various immunomodulation and immunosuppressive regimens. The finding of an optimal approach to immunorejection would potentially be applicable to actual clinical islet xenotransplantation in diabetic patients.

The long-term observation of the transplantation of encapsulated rat islets to the diabetic mice.

Rat islets encapsulated in the immuno-isolated membrane were transplanted intraperitoneally into 11 streptozotocin induced diabetic mice. The effective rate was 91% while all rejected in the 11 nonencapsulated xenograft group. 4 mice showed complete remission and longest normoglycemic period in those mice was 360 days. The pathological changes of islets of the long-term successful xenograft group were studied and showed atrophy. It proved that the immuno-isolated membrane can protect rejection during xeno-transplantation.

Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.

Evaluation of Microencapsulated Islets in Agarose Gel as Bioartificial Pancreas by Studies of Hormone Secretion in Culture and by Xenotransplantation

Islets were microencapsulated in agarose gel for examination of the possible use of microencapsulated islets as a bioartificial pancreas. Microencapsulated islets secreted insulin into the culture medium (RPMI-1640) and could rapidly increase their insulin release in response to a glucose challenge even after greater than 100 days. Hamster islets in groups of 400-1000 encapsulated in microbeads containing 11-14% (wt/wt) agarose were xenogenically transplanted into the peritoneal cavity of five diabetic mice. The longest normoglycemic period in these mice was 53 days, which was markedly longer than the normoglycemic period obtained by nonencapsulated islets. Agarose seems to be a suitable basic material for encapsulating islets, because the islets can easily be microencapsulated without any adverse effect on the islet function.

Microencapsulation of Langerhans Islets in Agarose Microbeads and Their Application for a Bioartificial Pancreas

Microencapsulation of islets is considered to be a promising approach to the development of a bioartificial pancreas. In this study agarose was examined as a material to microencapsulate islets. By a low-temperature gelation tech nique, islets can be easily microencapsulated into agarose microbeads without any adverse effect on the functions of islets. Encapsulated islets in agarose microbeads maintained their intact round shapes during the entire period of culturing. They secreted 50-70 μU islet-1 day -1 insulin into the culture medium and regulated insulin secretion minute by minute in response to the change of glucose concentration even after 140 days of in vitro culture. The molecular weight permeability of agarose microbeads can be modulated by changing the agarose concentration. Agarose microbeads containing higher than 10 wt% can hinder the penetration of bovine serum albumin (M.W. = 67,000), and thus can protect islets from the attack of immunoglobulin. Hamster islets encapsulated in microbeads containing 11 wt% agarose were xenogenically transplanted into the peritoneal cavity of a diabetic mouse. Before the transplantation plasma glucose levels were higher than 400 mg dL-1. After transplantation plasma glucose levels were normalized within two days and the normoglycemic period was 29 days. Although more studies are needed to prolong this period for bioartificial pancreas function, agarose is a prominent basic material for en capsulating islets.

Hyperglycemia decreases glucose uptake in type I diabetes.

It has recently been postulated that hyperglycemia per se may contribute to insulin resistance in diabetes. To examine this possibility directly, we measured glucose uptake after 24 h of hyperglycemia (281 +/- 16 mg/dl) and normoglycemia (99 +/- 6 mg/dl) in 10 type I (insulin-dependent) diabetic patients (age 33 +/- 3 yr, relative body wt 102 +/- 3%) treated with continuous subcutaneous insulin infusion. Hyperglycemia was induced by an intravenous glucose infusion, whereas saline was administered during the control day. During both studies the patient received a similar diet and insulin dose. After hyper- and normoglycemia, a primed continuous infusion of insulin (40 mU X m-2 X min-1) was started, and plasma glucose was adjusted to and maintained at 142 +/- 2 and 140 +/- 2 mg/dl, respectively, during 60-160 min of insulin infusion. The rate of glucose uptake after hyperglycemia averaged 8.3 +/- 1.1 mg X kg-1 X min-1, which was lower than the rate after the normoglycemic period (10.1 +/- 1.2 mg X kg-1 X min-1, P less than .001). In conclusion, short-term hyperglycemia reduces glucose uptake in type I diabetic patients. Thus, part of the glucose or insulin resistance in these patients may be caused by hyperglycemia per se.