Exercise in diabetic man: glucose turnover and free insulin responses after glycemic normalization with intravenous insulin

The metabolic response to moderate exercise in postabsorptive insulin-dependent diabetics receiving insulin by constant intravenous infusion was compared with that of normal controls. The diabetics were infused with insulin overnight and were normoglycemic (89 +/- 6 mg/dL, controls: 90 +/- 6 mg/dL). With exercise, glycemia remained constant in both groups. In the diabetic subjects, glucose production was 166 +/- 11 mg/min at rest, increased to 230 +/- 27 mg/min with exercise (p less than 0.05), and returned to base line during recovery. Glucose disappearance changed in a synchronous and parallel fashion. In the normal controls, insulin concentration was 0.44 +/- 0.03 ng/mL at rest and decreased significantly with exercise (p less than 0.01) while in the diabetic free insulin was fourfold higher (1.70 +/- 0.32) and did not change with exercise. Lactate increased similarly (twofold) with exercise in both groups. In summary, (i) complete normalization of glycemia, glucose turnover, and the lactate response to postabsorptive exercise can be achieved by the intravenous infusion of insulin adjusted to obtain normoglycemia before the onset of exercise; (ii) this response was obtained with an associated elevation in circulating free insulin which probably reflects the peripheral intravenous route rather than the physiologic (portal) site of insulin administration.     

Use of Glucose,Insulin, and C‐Reactive Protein to Determine Need for Glucose Tolerance Testing

Objective: Glucose intolerance has been shown to be a better predictor of morbidity and mortality than impaired fasting glucose. However, glucose tolerance tests are inconvenient and expensive. This study evaluated the relative frequencies of glucose intolerance and impaired fasting glucose and sought to determine if 2‐hour glucose could be predicted from simple demographic and laboratory data in an obese population. Research Methods and Procedures: Eighty‐nine obese subjects (median BMI 35 kg/m², range 30 to 40 kg/m²) underwent glucose tolerance testing. Using step‐wise linear and logistic regression analysis, fasting glucose, high‐sensitivity C‐reactive protein (hsCRP), fasting insulin, high‐density lipoprotein cholesterol, triglycerides, weight, height, BMI, waist circumference, hip circumference, waist‐to‐hip ratio, sex, and age were assessed as predictors of glucose intolerance. Results: Impaired glucose tolerance was more prevalent (27%) than impaired fasting glucose (5.6%). Only fasting glucose and hsCRP were significant (p < 0.05) independent predictors of impaired 2‐hour glucose (>140 mg/dL). A fasting glucose ≥ 100 mg/dL or an hsCRP > 0.32 mg/dL (upper quartile of the normal range) detected 81% (sensitivity) of obese subjects with impaired glucose tolerance; however, specificity was poor (46%). Fasting insulin ≥ 6 μU/mL had better sensitivity (92%) but poorer specificity (30%). Discussion: Impaired glucose tolerance is more common than impaired fasting glucose in an obese population. Possible strategies to avoid doing glucose tolerance tests in all obese patients would be to do glucose tolerance testing only in those whose fasting glucose is ≥ 100 mg/dL or whose hsCRP exceeds 0.32 mg/dL or those whose fasting insulin is ≥ 6 μU/mL.     

Improved insulin action following short-term exercise training: role of energy and carbohydrate balance.

Short-term exercise training improves insulin action, but the impact of replacing the energy expended during exercise to prevent energy deficit is unclear. The purpose of this study was to establish the role of an energy deficit in mediating improved insulin action after short-term exercise training. Two groups of previously sedentary, overweight/obese subjects performed 6 consecutive days of moderate-intensity walking to expend approximately 500 kcal/day. In one group, energy and carbohydrate expended during exercise was replaced [balance group (BAL), n = 8] and in the other group, energy was not replaced [deficit group (DEF), n = 8]. Insulin action (blood glucose uptake during glucose infusion) and selected lipids and adipokines were measured pre- and posttraining. Training increased estimated daily energy expenditure by approximately 500 kcal/day (DEF = 469 +/- 45, BAL = 521 +/- 48), generating an energy deficit in DEF (-481 +/- 24 kcal/day) but not BAL (+8 +/- 20 kcal/day). Insulin action increased 40% in DEF (P = 0.032) but not BAL (-8.4%, P = 0.107). Hepatic glucose production was suppressed during glucose infusion in DEF (30.2 +/- 9.5%, P = 0.037) but not BAL (-10.0 +/- 7.4%, P = 0.417). Fasting leptin concentrations declined in DEF but not BAL. Six days of exercise training without energy replacement significantly increased insulin action. Restoring energy balance by refeeding the energy and carbohydrate expended during exercise resulted in no change in insulin action. These findings suggest that changes in short-term energy and/or carbohydrate balance play a key role in mediating the beneficial effects of exercise on whole body and hepatic insulin action.     

Triglyceride, nonesterified fatty acids, and prediabetic neuropathy: role for oxidative-nitrosative stress

Peripheral neuropathy develops in human subjects with prediabetes and metabolic syndrome before overt hyperglycemia. The contributions of impaired glucose tolerance and insulin signaling, hypertriglyceridemia and/or increased nonesterified fatty acids (NEFA), and hypercholesterolemia to this condition remain unknown. Niacin and its derivatives alleviate dyslipidemia with a minor effect on glucose homeostasis. This study evaluated the roles of impaired glucose tolerance versus dyslipidemia in prediabetic neuropathy using Zucker fatty (fa/fa) rats and the niacin derivative acipimox, as well as the interplay of hypertriglyceridemia, increased NEFA, and oxidative-nitrosative stress. Sixteen-week-old Zucker fatty rats with impaired glucose tolerance, obesity, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and increased NEFA displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. Acipimox (100 mg kg(-1) day(-1), 4 weeks) reduced serum insulin, NEFA, and triglyceride concentrations without affecting glucose tolerance and hypercholesterolemia. It alleviated sensory nerve conduction velocity deficit and changes in behavioral measures of sensory function and corrected oxidative-nitrosative stress, but not impaired insulin signaling, in peripheral nerve. Elevated NEFA increased total and mitochondrial superoxide production and NAD(P)H oxidase activity in cultured human Schwann cells. In conclusion, hypertriglyceridemia and/or increased NEFA concentrations cause prediabetic neuropathy through oxidative-nitrosative stress. Lipid-lowering agents and antioxidants may find a use in the management of this condition.     

Influence of co-administration of oral insulin and docosahexaenoic acid in mice

Insulin and docosahexaenoic acid are both present in human milk. The aim of this study was to examine the effect of co-administration of oral insulin and DHA in mice. Immediately after weaning, Balb C mice were divided into four groups of seven mice each for a period of 4 weeks. Group 1 received a chow diet only. Group 2 received a chow diet and also was given human insulin (1 unit/mL of drinking water) without docosahexaenoic acid. Group 3 received a chow diet supplemented with docosahexaenoic acid (500 mg/kg/day in the chow) and no insulin. Group 4 received a chow diet and supplementation with both human insulin and docosahexaenoic acid. At 28 days, fasting blood levels of glucose, insulin, lipids, lipid peroxidation analysis, docosahexaenoic acid plasma levels, and docosahexaenoic acid content in red blood cells were determined. We found that glucose levels were lower in the group that was supplemented with insulin only (group 2, 61.4 mg/dL +/- 2.8,mean +/- SD) and in the group that was supplemented with DHA only (group 3, 61.1 mg/dL +/- 2.0) compared to controls (group 1, 71 mg/dL +/- 6.9, P < 0.0001). Supplementation of both insulin and docosahexaenoic acid (group 4) resulted in significantly lower glucose levels (56.4 mg/dL +/- 2.6) compared to those in groups 2 and 3 (P < 0.01). No significant differences were found in lipid profile or lipid peroxidation between the groups. We conclude that adding insulin or docosahexaenoic acid to the diet of weaned Balb C mice reduces glucose blood levels. Supplementation with both substances has a synergistic effect. The presence of insulin and docosahexaenoic acid in human milk may be the cause for reduced glucose levels in breast-fed infants, in addition to the known effects of DHA on insulin sensitivity.     

Insulin, somatomedin-C, human chorionic gonadotropin, and forskolin enhance glucose oxidation by granulosa cells

The long exposure times required to observe stimulatory effects of insulin on steroidogenesis and protein synthesis in granulosa cells suggested that these effects might be secondary to stimulation of another metabolic process. The present studies examined the effects of insulin, the insulin-like growth factor somatomedin-C (Sm-C), human chorionic gonadotropin (hCG), and forskolin, a compound that activates adenylyl cyclase independently of a receptor, on glucose metabolism. Granulosa cells from preovulatory porcine ovarian follicles were incubated at 37 degrees C in Dulbecco's phosphate-buffered saline supplemented with bovine serum albumin, vitamins, amino acids, and glucose (0.01-20 mM). Cells were incubated with [14C]glucose for up to 23 h with or without a prior 20-h preincubation. Oxidation of glucose, assessed by quantitation of 14CO2 produced, was dependent on time and concentration of glucose. Optimal glucose concentrations for glucose oxidation were 3 mM in the absence or presence of insulin and correlated well with the measured glucose concentrations in follicular fluid (3 mM). After a 20-h preincubation in the absence or presence of insulin (1 microM), the rates of CO2 production were 10.6 and 21.6 pmol/micrograms DNA/h for control and insulin-treated cells, respectively. Insulin had an EC50 of 164 nM. Sm-C and hCG were more potent stimulators than insulin with EC50s of 768 pM and 161 pM, respectively. The greater sensitivity of granulosa cells to Sm-C than to insulin supports the concept that insulin exerts its effect via reactivity with the Sm-C receptor. The effect of hCG may have been mediated by cyclic adenosine 3',5'-monophosphate (cAMP), since forskolin also enhanced 14CO2 production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma insulin and C-peptide responses to oral glucose load after physical exercise in men with normal and impaired glucose tolerance

Blood glucose, plasma insulin and C-peptide responses to oral glucose tolerance test (OGTT) were studied under basal conditions and immediately after 90-min exercise (60% VO2 max) in nondiabetic subjects with normal or impaired glucose tolerance. During the postexercise recovery blood glucose response to OGTT was increased in normal subjects and markedly decreased in those with impaired glucose tolerance, while insulin and C-peptide responses were diminished in both subgroups. The ratio of blood glucose to insulin was similarly elevated in all subjects. Comparing with basal conditions no significant changes were found in C-peptide to insulin ratio in response to OGTT after exercise, although a tendency towards an elevation of this ratio was noted in the subjects with impaired glucose tolerance. The data indicate that the reduced insulin response to OGTT during postexercise recovery in healthy subjects is due to diminished insulin secretion without any substantial changes in the hormone removal from blood, whereas in the glucose intolerant men the latter process may be enhanced.     

Influence of alternating extremely low frequency ELF magnetic field on structure and function of pancreas in rats.

The aim of this study was to estimate the influence on ultrastructure and function of endocrine and excretoric part of pancreas in rats of extremely low frequency alternating magnetic fields with parameters used in therapy in humans. The animals from the two experimental groups were exposed to a rectangular magnetic field waveform at a frequency of 10 Hz and induction of 1.8-3.8 mT--(group P) or a sinusoidal magnetic field at a frequency of 40 Hz and induction of 1.3-2.7 mT--(group S), respectively. The control rats were subjected to sham exposure. The cycle of 1, 3, 6, 9, and 14 daily exposure sessions lasting 30 min was made in all groups. Some of rats after finishing the cycle of 14 exposures were left in the same conditions except for the magnetic field for 3 or 10 days. In both groups of rats exposed to magnetic field, a distinct tendency to decrease glucose concentration, compared to control group, was observed during the exposure cycle. Serum glucose became normal after the end of exposure sessions. The concentrations of insulin in both groups of rats exposed to magnetic field were significantly higher, compared to the controls, during the exposure cycle. After the end of exposure cycle the concentration of insulin in group S became normal. In contrast, in group P the concentration of insulin decreased significantly on the last day of exposure, with a subsequent increase in the following days. The activity of alpha-amylase and lipase in the serum of experimental and control rats was not affected. In both groups of exposed rats, reversible changes of ultrastructure of the pancreatic islets, including expansion of the Golgi apparatus, extension of rough endoplasmatic reticulum, mitochondrial swelling, expansion of beta-granules and increase in number of empty vesicles in beta cells, occurred during the exposure. In acinar cells of exposed animals, a slight extension of rough endoplasmatic reticulum and mitochondrial swelling as transitory changes were observed. The structural and functional changes in pancreas are probably adaptative ones.     

The effect of a single-circuit weight-training session on the blood biochemistry of untrained university students

The metabolic and hormonal responses to an intensive single-circuit weight-training session were studied in 15 untrained male students. The training programme consisted of ten exercises, employing all the large groups of muscles. Students performed three circuits using a work-to-rest ratio of 30 s:30 s at 70% of one-repetition maximum. The whole programme lasted 30 min. Blood samples were obtained from the anticubital vein 30 min before exercise, immediately after exercise finished and after 1-h, 6-h, and 24-h periods of recovery. The training session produced significant increases in the plasma adrenocorticotropic hormone, cortisol, aldosterone, testosterone, progesterone and somatotropin concentrations. The plasma level of insulin and C-peptide remained unchanged. The strength exercises caused elevated ratios of cortisol:testosterone and cortisol:insulin, indicating a prevalence of stimulation of catabolic processes as well as of mobilization of energy reserves but during the recovery period the reverse of this was observed. Immediately after exercise the mean lactate concentration was 7.19 mmol.l-1, SD 0.56, the glucose concentration increased significantly during exercise and decreased rapidly during recovery. The high density lipoprotein-cholesterol increased in 1-h period of recovery compared with the initial level. The concentration of total cholesterol, low density lipoprotein-cholesterol and triglyceride, did not change. Packed cell volume did not change during exercise or recovery.     

Different Diabetogenic Response to Moderate Doses of Streptozotocin in Pregnant Rats,and Its Long-Term Consequences in the Offspring

Diabetes during pregnancy results in congenital malformations and long-term postnatal diseases. Experimental models are still needed to investigate the mechanism responsible for these alterations. Thus, by the administration of different doses of streptozotocin (STZ) (0, 25, 30, or 35 mg/kg body weight, intravenous) at the onset of pregnancy in rats, the present study sought an appropriate animal model for this pathology. At day 6 of pregnancy, plasma glucose was progressively higher with an increasing STZ dose, and in rats receiving the 35-mg dose, 2 subgroups were detected: some animals had plasma glucose levels above controls but below 200 mg/dL (mildly diabetic, MD), whereas others had levels above 400 mg/dL (severely diabetic, SD). At day 20 of pregnancy, the MD rats had normal glycemia, but after an oral glucose load (2 g/kg body weight), plasma glucose increased more and insulin increased less than in controls. The SD rats maintained their hyperglycemia and had a greatly impaired oral glucose tolerance. At day 20, fetuses of SD dams were fewer, weighed less, and had enhanced plasma glucose and triglycerides and decreased insulin, whereas those from MD dams did not differ from controls. At birth, newborns from MD dams had higher body weight, plasma insulin, and liver triglycerides as well as total body lipid concentrations than controls, and on day 21, remained macrosomic and showed higher plasma glucose and liver triglyceride concentrations. At 70 days of age, offspring of MD dams had impaired oral glucose tolerance but normal plasma insulin change in the case of females, whereas plasma insulin increased less in males. These alterations were manifest more in those offspring from dams that had > 50% macrosomic newborns than in those from dams that had < 50% macrosomic newborns. In conclusion, whereas our MD rats mimic the changes taking place in gestational diabetic women and show the long-term risk of macrosomia, the SD rats are more similar to uncontrolled diabetics. Thus these two rat models, obtained with moderate amounts of STZ, could be used to study the pathophysiological consequences of these different diabetic conditions.     

Dietary fat type alters glucose metabolism in isolated rat hepatocytes

Dietary fat type can influence the regulation of carbohydrate metabolism in multiple tissue types. The influence of feeding high-fat (40% of kilocalories) diets containing either menhaden oil (MO) or coconut oil (CO) on hepatic glycogenolytic and gluconeogenic capacities was studied in isolated rat hepatocytes. Estimates of both glycogenolytic and gluconeogenic capacities were performed on hepatocytes isolated from fed and fasted animals, respectively. In MO-fed animals, both basal and hormone-stimulated rates of glucose production were significantly greater than those in CO-fed animals. However, both groups displayed a similar maximal increase in glucose production above basal for glucagon and epinephrine (2.3- and 1.9-fold, respectively). Basal rates of adenosine 3′,5′-cyclic phosphate (cAMP) production were not different between groups whereas glucagon-stimulated cAMP production was increased twofold in the MO-fed group. In both MO and CO groups, the addition of 10 nM insulin reduced glucose production in fed animals to similar absolute rates. In animals fasted for 24 hours, gluconeogenic capacity was estimated using 10 mM pyruvate, lactate, or glycerol. Glucose production from all substrates was significantly greater in CO-fed animals. In addition to increased gluconeogenic rates, maximal phosphoenolpyruvate carboxykinase (PEPCK) activity was increased in the CO-fed group. Insulin reduced glucose production in both dietary groups, but the absolute rate of glucose production was 28% greater in the CO-fed group relative to the MO-fed group. In summary, dietary fat type can markedly influence the regulation of hepatic glucose metabolism in multiple metabolic pathways. MO feeding promoted glycogenolysis and sensitivity to insulin whereas CO feeding favored gluconeogenesis and reduced insulin sensitivity.     

The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse

Obesity is typically associated with elevated levels of free fatty acids (FFAs) and is linked to glucose intolerance and type 2 diabetes. FFAs exert divergent effects on insulin secretion from beta cells: acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs insulin secretion. The G protein-coupled receptor GPR40 is selectively expressed in beta cells and is activated by FFAs. We show here that GPR40 mediates both acute and chronic effects of FFAs on insulin secretion and that GPR40 signaling is linked to impaired glucose homeostasis. GPR40-deficient beta cells secrete less insulin in response to FFAs, and loss of GPR40 protects mice from obesity-induced hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, increased hepatic glucose output, hyperglycemia, and glucose intolerance. Conversely, overexpression of GPR40 in beta cells of mice leads to impaired beta cell function, hypoinsulinemia, and diabetes. These results suggest that GPR40 plays an important role in the chain of events linking obesity and type 2 diabetes.     

Effects of cadmium exposure on morphological aspects of pancreas,weights of fetus and placenta in streptozotocin-induced diabetic pregnant rats

This study was designed to evaluate the effects of Cd exposure on morphological aspects of β-cell and weights of fetus and placenta in streptozotocin (STZ)-induced diabetic pregnant rats. Ninety-nine virgin female Wistar rats (200–220 g) were mated with 33 males for at least 12 h. From the onset of pregnancy, the rats were divided into four experimental groups (control, Cd treated, STZ treated, and Cd+STZ treated). The Cd-treated group was injected subcutaneously daily with CdCl₂ dissolved in isotonic NaCl, starting at the onset of pregnancy throughout the experiment. Diabetes was induced on the 13th d of pregnancy by a single intraperitoneal injection of STZ in STZ-treated group. In addition to the daily injection of Cd, a single intraperitoneal injection of STZ was also given on the 13th d of pregnancy in the Cd+STZ-treated group. The rats received the last injection 24 h before being sacrificed and 10 randomly selected rats in each group were sacrificed on the 15th and 20th d of pregnancy. Blood samples were taken for the determination of the serum glucose and insulin levels. Maternal pancreases, fetuses, and placentas of sacrificed rats in all groups were harvested (fetal pancreas was also harvested only on the 20th d of pregnancy) for morphological and immunohistochemical examinations. Cd exposure alone caused a degeneration, necrosis, and weak degranulation, but Cd exposure with STZ caused a severe degeneration, necrosis, and degranulation in the β-cells of the pancreatic islets. No morphological or immunohistochemical differences were found in β-cells of fetal pancreatic islets of control or other treatment groups. Cd exposure alone also decreased the fetal and placental weights. The administration of STZ alone, on the other hand, increased the placental weight. Cd, STZ, and Cd+STZ administration increased the glucose and decreased the insulin level. The increase in glucose and decrease in insulin levels were higher when Cd and STZ were given together. All of these changes were more severe on the 20th d than those on the 15th d of the pregnancy. It is concluded that Cd exposure during pregnancy may reduce the birth and placental weights and produce necrosis, degeneration, and degranulation in β-cells of pancreatic islets, causing an increase in the serum glucose level. These changes might be severe in diabetic pregnant mothers.     

Circadian Variation in Alloxan Sensitivity of Mice as Indicated by Mortality and Blood Glucose Alteration

The objective of this study was to determine in mice if a time-dependent pancreatic β-cell susceptibility to alloxan could be correlated to daily changes in blood glucose levels and to monitor the pattern of blood glucose at various times of day as mice became diabetic. Food was removed from mice standardized to a 12-h light:dark cycle (lights on at 0600 h CST, during the month of June) at 12 h before subcutaneous injection with 0.27 mg/g of alloxan. Six groups of 30 fasted mice were injected at 4-h intervals. Blood glucose levels were measured from each group immediately prior to injection, and at 2, 4, 8, 12, 24, 48, and 216 h after treatment. Animals receiving alloxan during the early- to middark period had an increase in blood glucose after 2 h, followed by a decline to hypoglycemic levels between 4 and 8 h, and recovery to hyperglycemic levels 48 h after alloxan exposure. Three and 30% of these animals were dead at 8 and 48 h, respectively. Mice treated during the midlight span had decreased blood glucose levels 2 h after alloxan treatment followed by an increase to diabetic hyperglycemia within 48 h. Twenty-three and 70% of the animals treated at 1430 h were dead at 8 and 48 h, respectively. At 216 h, total mortality was 45.6% and 81 of the 98 surviving mice were hyperglycemic. These data suggest a greater sensitivity to alloxan during the midlight resting period of the mice. This may be the result of increased sensitivity to the insulin released from the β cells when alloxan was given during the light span.     

Effects of soy protein and genistein on blood glucose, antioxidant enzyme activities, and lipid profile in streptozotocin-induced diabetic rats

In the current study, the effect of soy protein and genistein, one of the main isoflavones in soybeans, on blood glucose, lipid profile, and antioxidant enzyme activities in streptozotocin (STZ)-induced diabetic rats was investigated. Male Sprague-Dawley rats were divided into nondiabetic control, STZ, STZ-genistein supplemented group (STZ-G; 600 mg/kg diet), and STZ-isolated soy protein supplemented group (STZ-ISP; 200 g/kg diet). Diabetes was induced by a single injection of STZ (50 mg/kg BW) freshly dissolved in 0.1 mol/L citrate buffer (pH 4.5) into the intraperitonium. Diabetes was confirmed by measuring the fasting blood glucose concentration 48-h post-injection. The rats with blood glucose level above 350 mg/dL were considered to be diabetic. Genistein and ISP were supplemented in the diet for 3 weeks. The supplementation of genistein and ISP increased the plasma insulin level but decreased the HbA(IC) level of the STZ-induced diabetic rats. The supplementation of genistein and ISP increased the glucokinase level of the STZ-induced diabetic rats. A significant reduction in glucose-6-phosphatase was observed in the groups treated with genistein and ISP in comparison with the diabetic control group. Hepatic superoxide dismutase, catalase, and glutathione peroxidase activities of the STZ-induced diabetic rats were significantly decreased in comparison with the control rats. Administering genistein and ISP to the STZ-induced diabetic rats significantly increased those enzyme activities. The concentration of thiobarbituric acid reactive substances in the STZ-induced diabetic rats was significantly elevated, while the genistein and ISP supplement decreased it to the control concentration. Genistein and ISP supplements seem to be beneficial for correcting the hyperglycemia and preventing diabetic complications.     

Glucose regulation in captive Pongo pygmaeus abeli,P. p. pygmaeus,andP. p. abeli x P. p. pygmaeus orangutans

Intravenous glucose tolerance tests (IVGTT) were performed on 30 anesthetized, captive Sumatran (Pongo pygmaeus abeli), Bornean (P. p. pygmaeus), and hybrid (P. p. ablie x P. p. pygmaeus) orangutans, and fasted blood samples were taken from two additional juvenile orangutans in 11 U.S. zoos from 1989 to 1997. The age range of animals was 3.5 to 40.5 years. Plasma and serum samples were assayed for glucose and insulin concentrations. Glucose disappearance rate (K_G), an index of glucose tolerance, was calculated, as were the early (acute) and second phase insulin responses to administered glucose. The mean ± SE (and median) fasting glucose and insulin concentrations were 113 ± 16 mg/dL (90 mg/dL) and 45 ± 7 μU/mL (27 μU/mL), respectively. Two animals previously suspected to be diabetic were easily identified by their markedly elevated fasting glucose concentrations (380 and 562 mg/dL) and relatively low fasted insulin concentrations (21 and 14 μU/mL); their insulin responses during the IVGTTs were also low or non‐detectable. Without these diabetics, the mean ± SE (median) fasting glucose concentration was 92 ± 18 mg/dL (89 mg/dL). Two animals, ages 18 and 40, were identified as potentially pre‐diabetic based on age, adiposity, elevated fasted glucose (116 and 137 mg/dL, respectively), and elevated fasted insulin concentrations (114 and 217 μU/mL, respectively). In addition, nearly half of the animals of varying ages, all sub‐species and both sexes exhibited delayed or attenuated acute insulin responses during the IVGTTs, resulting in lower K_G (P < 0.04) and suggesting propensity for glucose intolerance in captive orangutans. Glucose and insulin concentrations and insulin responses to glucose did not differ between females on hormonal contraception regimes and those not receiving treatment. Zoo Biol 19:193–208, 2000. © 2000 Wiley‐Liss, Inc.     

Comparison of 3 Algorithms for Basal Insulin in Transitioning from Intravenous to Subcutaneous Insulin in Stable Patients after Cardiothoracic Surgery

ObjectiveTo determine the effectiveness of an algorithm containing 1 of 3 initial subcutaneous doses of insulin detemir and flexible prandial and supplemental insulin aspart in stable patients who have undergone cardiac surgery and are being transitioned off intravenous insulin infusion.MethodsPatients were extubated, were not taking vasopressors, and were otherwise stable, requiring at least 1 unit per hour of intravenous insulin at least 48 hours after surgery. Patients were randomly assigned to once-daily insulin detemir at 50%, 65%, or 80% of intravenous basal insulin requirements and received insulin aspart according to carbohydrate intake. The dose of insulin detemir was adjusted daily over 72 hours.ResultsEighty-two patients were included. The percentages of patients with an initial morning glucose concentration of 80 to 130 mg/dL were 36%, 63%, and 56% of patients at the 50%, 65%, and 80% doses, respectively (P = .12). However, the mean overall glucose value at 24 and 72 hours was similar between groups, and 86%, 93%, and 92% of patients in each group, respectively, achieved a mean glucose concentration of 80 to 180 mg/dL at 72 hours (P = .60). Hypoglycemia (glucose < 65 mg/dL) only occurred in the 65% group (21%) and the 80% group (12%) over the first 72 hours (P = .02 in the 50% group compared with the 65% and 80% groups combined) with 1 event of a glucose concentration less than 40 mg/dL in the 80% group. There was no loss of glycemic control by the end of the once-daily dosing interval.ConclusionsGlycemic targets can be achieved without hypoglycemia by 72 hours in most patients who have undergone cardiac surgery and require intravenous insulin with a regimen consisting of an initial insulin detemir dose of 50% of basal intravenous insulin requirements and prandial and supplemental insulin. (Endocr Pract. 2011; 17:753-758)     

Endothelial cell and platelet bioenergetics: effect of glucose and nutrient composition

It has been suggested that cells that are independent of insulin for glucose uptake, when exposed to high glucose or other nutrient concentrations, manifest enhanced mitochondrial substrate oxidation with consequent enhanced potential and generation of reactive oxygen species (ROS); a paradigm that could predispose to vascular complications of diabetes. Here we exposed bovine aortic endothelial (BAE) cells and human platelets to variable glucose and fatty acid concentrations. We then examined oxygen consumption and acidification rates using recently available technology in the form of an extracellular oxygen and proton flux analyzer. Acute or overnight exposure of confluent BAE cells to glucose concentrations from 5.5 to 25 mM did not enhance or change the rate of oxygen consumption (OCR) under basal conditions, during ATP synthesis, or under uncoupled conditions. Glucose also did not alter OCR in sub-confluent cells, in cells exposed to low serum, or in cells treated with added pyruvate. Likewise, overnight exposure to fatty acids of varying saturation had no such effects. Overnight exposure of BAE cells to low glucose concentration decreased maximal uncoupled respiration, but not basal or ATP related oxygen consumption. Labeled glucose oxidation to CO(2) increased, but only marginally after high glucose exposure while oleate oxidation to CO(2) decreased. Overnight exposure to linolenic acid, but not oleic or linoleic acid increased extracellular acidification consistent with enhanced glycolytic metabolism. We were unable to detect an increase in production of reactive oxygen species (ROS) from BAE cells exposed to high medium glucose. Like BAE cells, exposure of human platelets to glucose did not increase oxygen consumption. As opposed to BAE cells, platelet mitochondria demonstrate less respiratory reserve capacity (beyond that needed for basal metabolism). Our data do not support the concept that exposure to high glucose or fatty acids accelerates mitochondrial oxidative metabolism in endothelial cells or platelets.     

Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake.

The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing, impairment of insulin action on muscle glucose transport and uptake. Thus maximal insulin-stimulated glucose uptake at 12 mM-glucose decreased from 34.8 +/- 1.9 to 11.5 +/- 1.1 mumol/h per g (mean +/- S.E.M., n = 10) during 5 h perfusion. This decrease in glucose uptake was accompanied by a similar change in muscle glucose transport as measured by uptake of 3-O-[14C]-methylglucose. Simultaneously, muscle glycogen stores increased to 2-3.5 times initial values, depending on fibre type. Perfusion for 5 h in the presence of glucose but in the absence of insulin decreased subsequent insulin action on glucose uptake by 80% of the effect of glucose with insulin, but without an increase in muscle glycogen concentration. Perfusion for 5 h with insulin but without glucose, and with subsequent addition of glucose back to the perfusate, revealed glucose uptake and transport similar to initial values obtained in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.     

Contribution of the Dawn Phenomenon to the Fasting and Postbreakfast Hyperglycemia In Type 1 Diabetes Treated With Once-Nightly Insulin Glargine

ObjectiveTo observe the effect of the dawn phenomenon on basal glucose and postbreakfast hyperglycemia in patients with type 1 diabetes treated with once-nightly insulin glargine and premeal insulin lispro.MethodsIn 49 study subjects consuming a fixed isocaloric (50% carbohydrate) diet of usual food, the insulin glargine dose was titrated from daily continuous glucose monitoring downloads to achieve a basal glucose goal of < 130 mg/dL 4 hours after meals and during serial meal omissions but with fewer than 10% of readings at < 70 mg/ dL during 24 hours. Patients also performed self-monitoring of plasma glucose 7 times a day (before and 2 hours after each meal or omitted meal and at bedtime).ResultsThe target mean basal glucose level was achieved only during the non-dawn phenomenon period (1400 hours to 0400 hours). During the dawn phenomenon, the mean (standard deviation) basal glucose level increased from 118 (57) mg/dL at 0400 hours to 156 (67) mg/dL before the breakfast meal, a 32% increase (P = .00149). The mean self-monitored plasma glucose level with meal omission was 63.8% of that increase with a breakfast meal.ConclusionThe fasting morning glucose concentration is considerably elevated because of the dawn phenomenon. Targeting insulin titration to this glucose level may result in excessive basal insulin dosing for the non-dawn phenomenon periods of the day. The dawn phenomenon is a large component of the postbreakfast hyperglycemia. Rather than increasing the morning premeal insulin bolus, consideration should be given to pretreating the earlier dawn phenomenon with an insulin pump with use of a variable basal insulin rate. (Endocr Pract. 2012;18:558-562)