Higher Insulin Infusion Rates Research Articles

Effectiveness of an Intravenous Insulin-Based Treatment Protocol for the Management of Hypertriglyceridemia-Associated Acute Pancreatitis.

There is burgeoning interest in intravenous insulin for hypertriglyceridemia-induced acute pancreatitis (HTG-AP) as a less invasive alternative to plasmapheresis; however, there are few published descriptions of disease-specific insulin protocols. To compare the efficacy and safety of an insulin infusion-based protocol with nonstandardized medical therapy for HTG-AP. This is a retrospective analysis before and after creation of an HTG-AP-specific insulin infusion treatment protocol. Inclusion criteria were age ≥18 years, an initial triglyceride level >1000 mg/dL, and a diagnosis of AP. The primary outcome of the study was time to a triglyceride level ≤1000 mg/dL. Sixty-seven patients were included in this study (26 pre-protocol and 41 in the HTG-AP insulin protocol group). Baseline characteristics between the groups were similar, with median initial triglyceride levels >3500 mg/dL. There was a trend toward patients treated with the HTG-AP-specific infusion reaching a triglyceride level ≤1000 mg/dL faster (43.3 [24.9-72.1] vs 26.9 [17.7-51.1] hours; P = 0.07). Those treated to ≤500 mg/dL achieved this faster with the disease-specific infusion (49.2 [29.4-67.8] vs 70.9 [36.3-107.2] hours, P = 0.04). Hypoglycemia was numerically lower in the HTG-AP-specific insulin infusion group despite higher insulin infusion rates (7.3% vs 19.2%). No patient in the HTG-AP-specific protocol group required plasmapheresis. The use of an HTG-AP-specific insulin infusion protocol, compared with antecedent nonstandardized care, resulted in prompter achievement of a triglyceride level ≤500 mg/dL and a strong trend toward faster achievement of ≤1000 mg/dL without an increased risk of hypoglycemia. While intravenous insulin may be considered the initial medical therapy for HTG-AP, further studies are needed to determine the optimal dosing.

Assessment of Insulin Infusion Requirements in COVID-19-Infected Patients With Diabetic Ketoacidosis

Background/ObjectiveCoronavirus disease 2019 (COVID-19) is thought to contribute to diabetic ketoacidosis (DKA) and worse outcomes in patients with diabetes. This study compared the cumulative insulin dose required to achieve DKA resolution in the intensive care unit among patients with type 2 diabetes and COVID-19 infection versus without COVID-19 infection. MethodsThis retrospective cohort study evaluated 100 patients—50 patients with COVID-19 in cohort 1 and 50 patients without COVID-19 in cohort 2—treated with insulin infusions for DKA at a tertiary care teaching hospital. The primary outcome was to compare the cumulative insulin dose required to achieve DKA resolution in each cohort. The secondary outcomes included time to DKA resolution, mean insulin infusion rate, and mean weight-based cumulative insulin infusion dose required to achieve DKA resolution. All endpoints were adjusted for confounders. ResultsThe mean cumulative insulin dose was 190.3 units in cohort 1 versus 116.4 units in cohort 2 (P = .0038). Patients receiving steroids had a mean time to DKA resolution of 35.9 hours in cohort 1 versus 15.6 hours in cohort 2 (P = .0014). In cohort 1 versus cohort 2, the mean insulin infusion rate was 7.1 units/hour versus 5.3 units/hour (P = .0025), whereas the mean weight-based cumulative insulin infusion dose was 2.1 units/kg versus 1.5 units/kg (P = .0437), respectively. ConclusionCOVID-19-infected patients required a significantly larger cumulative insulin dose, longer time to DKA resolution, higher insulin infusion rate, and higher weight-based insulin infusion dose to achieve DKA resolution versus non–COVID-19-infected patients with type 2 diabetes.

Patients with Type 1 Diabetes Treated with Insulin Pumps Need Widely Heterogeneous Basal Rate Profiles Ranging from Negligible to Pronounced Diurnal Variability

Pump-treated patients with type 1 diabetes have widely differing basal insulin infusion profiles. We analyzed consequences of such heterogeneity for glycemic control under fasting conditions. Data from 339 adult patients with type 1 diabetes on insulin pump therapy undergoing a 24-hour fast (basal rate test) were retrospectively analyzed. Hourly programmed basal insulin infusion rates and plasma glucose concentrations as well as their proportions within, below, or above arbitrarily defined target ranges were assessed for specific periods of the day (eg, 1-7 hours, "dawn" period, 16-19 hours, "dusk" period, reference period 20-1 hours/10-14 hours), by tertiles of a predefined "dawn" index (mean basal insulin infusion rate during the "dawn" divided by the reference periods). The "dawn" index varied interindividually from 0.7 to 4.4. Basal insulin infusion profiles exhibited substantial differences (P = .011), especially overnight. Despite higher insulin infusion rates at 4 and 6.45 hours, patients with the most pronounced "dawn" phenomenon exhibited higher plasma glucose concentrations at those time points (P < .012). Patients with a marked "dawn" phenomenon exhibited a lower probability for low (<4.4 mmol/L) and a higher probability of high values (>7.2 mmol/L) during the dawn period (all P values <.01). We observe substantial interindividual heterogeneity in the "dawn" phenomenon. However, widely different empirically derived basal insulin infusion profiles appear appropriate for individual patients, as indicated by similar plasma glucose concentrations, mainly in the target range, during a 24-hour fasting period.

Higher insulin infusion rate but not 24-h insulin consumption is associated with hypoglycemia in critically ill patients

AimsTo assess the association between insulin infusion rates, and 24-h insulin consumption on hypoglycemia in the intensive care unit (ICU). MethodsThis was a retrospective case–control study, conducted at an academic institution in the United States. Adult patients admitted to the ICU receiving intravenous insulin infusions for blood glucose control were included. Hypoglycemic (blood glucose <70mg/dL) patients were matched 1:1 with non-hypoglycemic controls based on age, gender, and body mass index. Multivariable conditional logistic regression analyses were conducted to determine the effect of: (1) weight-adjusted insulin infusion rate (units/kg/h), (2) non-weight-adjusted insulin infusion rate (units/h), or (3) 24-h insulin consumption (units/day) on hypoglycemia. ResultsA total of 122 patients were included in the study (61 cases, 61 controls). Compared to those patients who received <0.05 units/kg/h, the odds of hypoglycemia was higher in those who received was ≥0.1 units/kg/h (OR 4.57, 95% CI 1.45–14.41, p=0.010). Compared to those patients who received <4 units/h, the odds of hypoglycemia was higher in those who received was ≥8 units/h (4.17, 95% CI 1.18–14.75, p=0.027). The risk of hypoglycemia did not increase with higher 24-h insulin consumption. ConclusionsHigher insulin infusion rates rather than 24-h insulin consumption may be associated with hypoglycemia in critically ill patients in the ICU.

The effects of acute hyperinsulinemia on bone metabolism

Insulin signaling in bone-forming osteoblasts stimulates bone formation and promotes the release of osteocalcin (OC) in mice. Only a few studies have assessed the direct effect of insulin on bone metabolism in humans. Here, we studied markers of bone metabolism in response to acute hyperinsulinemia in men and women. Thirty-three subjects from three separate cohorts (n=8, n=12 and n=13) participated in a euglycaemic hyperinsulinemic clamp study. Blood samples were collected before and at the end of infusions to determine the markers of bone formation (PINP, total OC, uncarboxylated form of OC (ucOC)) and resorption (CTX, TRAcP5b). During 4 h insulin infusion (40 mU/m2 per min, low insulin), CTX level decreased by 11% (P<0.05). High insulin infusion rate (72 mU/m2 per min) for 4 h resulted in more pronounced decrease (−32%, P<0.01) whereas shorter insulin exposure (40 mU/m2 per min for 2 h) had no effect (P=0.61). Markers of osteoblast activity remained unchanged during 4 h insulin, but the ratio of uncarboxylated-to-total OC decreased in response to insulin (P<0.05 and P<0.01 for low and high insulin for 4 h respectively). During 2 h low insulin infusion, both total OC and ucOC decreased significantly (P<0.01 for both). In conclusion, insulin decreases bone resorption and circulating levels of total OC and ucOC. Insulin has direct effects on bone metabolism in humans and changes in the circulating levels of bone markers can be seen within a few hours after administration of insulin.

Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels.

Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P < 0.001). EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.

Whole body insulin responsiveness is higher in beef steers selected for increased muscling

The aim of this experiment was to evaluate the impact of selection for greater muscling on whole body insulin responsiveness in cattle, as reflected by greater uptake of glucose in response to constant insulin infusion and greater glucose disappearance following an intravenous glucose tolerance test. This study used 18-month-old steers from an Angus herd visually assessed and selected for divergence in muscling over 15 years. Eleven high-muscled (High), 10 low-muscled (Low) and 3 high-muscled steers, which were heterozygous for a myostatin polymorphism (HighHet), were infused with insulin using the hyperinsulineamic-euglyceamic clamp technique. Insulin was constantly infused at two levels, 0.6 μIU/kg per min and 6.0 μIU/kg per min. Glucose was concurrently infused to maintain euglyceamia and the steady state glucose infusion rate (SSGIR) indicated insulin responsiveness. An intravenous glucose tolerance test was also administered at 200 mg/kg live weight. Sixteen blood samples were collected from each animal between −30 and 130 min relative to the administration of intravenous glucose, plasma glucose and insulin concentration was determined in order to analyse insulin secretion and glucose disappearance. Insulin-like growth factor-1 (IGF-1) was also measured in basal plasma samples. At the low insulin infusion rate of 0.6 mU/kg per min, the SSGIR was 73% higher for the High muscling genotype animals when compared to the Low (P < 0.05). At the high insulin infusion rate of 6.0 mU/kg per min, these differences were proportionately less with the High and the HighHet genotypes having only 27% and 34% higher SSGIR (P < 0.05) than the Low-muscled genotype. The High-muscled cattle also had 30% higher plasma IGF-1 concentrations compared to the Low-muscled cattle. There was no effect of muscling genotype on basal insulin or basal glucose concentrations, glucose disappearance or insulin secretion following an intravenous glucose tolerance test. The increased whole body insulin responsiveness in combination with higher IGF-1 concentrations in the High-muscled steers is likely to initiate a greater level of protein synthesis, which may partially explain the increased muscle accretion in these animals.

Cleveland Clinic Cardiovascular Intensive Care Unit Insulin Conversion Protocol

The importance of near-normal blood glucose in the immediate postoperative period is generally accepted and is best achieved in the perioperative period with a constant intravenous (IV) infusion of insulin. This requires intensive nursing only achievable in an intensive care unit (ICU) setting. Glucose management after transfer to a regular nursing floor (RNF) has not been studied systematically. In August 2006, the Cleveland Clinic began using long-acting insulin glargine as the insulin infusion was terminated in the ICU. This prospective analysis examined all patients receiving IV insulin infusion after cardiothoracic surgery in a 1 month period. The analyses evaluated the safety and efficacy of a protocol using a transition to subcutaneous insulin glargine of 50% of the calculated 24 h requirement at the end of the ICU insulin infusion protocol in preparation for transfer to the RNF. Only 1 patient in 99 developed hypoglycemia, and no patient suffered severe hypoglycemia (glucose < 40 mg/dl), while the majority (70%) had euglycemia (glucose between 70 and 150 mg/dl). This approach was both safe-as there was very little hypoglycemia (1 patient in 99)-and effective, as blood sugar was well controlled in most subjects. Efficacy for achieving euglycemia was 70%. Efficacy was likely reduced because of the upper limit of insulin glargine dosage imposed by some providers as a safety consideration. Although there was a physician option to override, the maximum protocol dose of 30 U was rarely exceeded, leading to inadequate dosing in some subjects who required high insulin infusion rates in the ICU.

Acute hyperinsulinemia inhibits intramyocellular triglyceride synthesis in high-fat-fed obese rats

Hyperinsulinemia is common in obesity, but whether it plays a role in intramyocellular triglyceride (imcTG) buildup is unknown. In this study, hyperinsulinemic-euglycemic clamp experiments were performed in overnight-fasted lean and high-fat-fed obese rats, awake, to determine the effect of insulin on imcTG synthesis (incorporation of [(14)C]glycerol, [(14)C]glucose, and [(3)H]oleate). Insulin infusion at 25 (low insulin) and 100 (high insulin) pmol/kg/min increased plasma insulin by 5- and 16-fold, respectively, whereas plasma and intramyocellular glycerol, FFAs, triglycerides, and glucose levels were maintained at their basal levels by co-infusion of exogenous glycerol, FFAs, and triglycerides at fixed rates and glucose at varying rates. In obese rats, insulin suppressed incorporation of glycerol into the imcTG-glycerol moiety dose dependently (P < 0.01-P < 0.001) in gastrocnemius and tibialis anterior, but only the high insulin suppressed it in soleus (P < 0.05). The low insulin suppressed glucose incorporation into imcTG-glycerol in all three muscles (P = 0.01-P < 0.01). However, the low insulin did not affect (P > 0.05) and the high insulin suppressed (P < 0.05-P < 0.01) fatty acid incorporation into imcTG in all three muscles. Insulin also suppressed glycerol incorporation in lean rats (P < 0.01-P < 0.04). On the other hand, imcTG pool size was not affected by insulin (P > 0.05). These observations suggest that acute hyperinsulinemia inhibits imcTG synthesis and thus does not appear to promote imcTG accumulation via the synthetic pathway, at least in the short term.

Short-term ingestion of Ginkgo biloba extract does not alter whole body insulin sensitivity in non-diabetic, pre-diabetic or type 2 diabetic subjects—A randomized double-blind placebo-controlled crossover study

Ingestion of Ginkgo biloba Extract (EGb 761) may increase pancreatic beta-cell function in both healthy subjects with normal glucose tolerance (NGT) as well as patients with Type 2 Diabetes mellitus (T2DM). Since hyperinsulinemia is a hallmark of T2DM, it is important to verify that increased insulin production is not due to increased insulin resistance. NGT subjects (n = 10; age, 44.2 +/- 13.9 years old), impaired glucose tolerance (IGT) (n = 8; age 51.3 +/- 6.6 years old) and T2DM subjects (n = 8, 51.6 +/- 15.2 years old) completed a randomized, double-blind, placebo-controlled crossover study. After ingesting either EGb 761 (120 mg/day as a single dose) or placebo during each 3-month arm, a 2-step euglycemic insulin clamp was performed. At the low insulin infusion rate (10 mU/m2/min) the glucose metabolic rates (M values) were 3.5 +/- 1.5 vs. 3.0 +/- 0.5 mg/kg (P = 0.16), 3.0 +/- 0.4 vs. 2.8 +/- 0.8 mg/kg (P = 0.19) and 2.6 +/- 0.7 vs. 2.4 +/- 0.5 mg/kg (P = 0.09) for the placebo and EGb 761 cycles, in the NGT, IGT and T2DM subjects, respectively. At the high insulin infusion rate (40 mU/m2/min) the M values were 7.3+/-2.3 vs. 8.1 +/- 2.5mg/kg (P = 0.07), 6.2 +/- 1.6 vs. 6.5 +/- 2.1 mg/kg (P = 0.32) and 3.6 +/- 1.6 vs. 3.5 +/- 1.0 mg/kg (P = 0.34) for placebo vs. EGb 761 cycles, in the NGT, IGT and T2DM subjects, respectively. The ingestion of 120 mg of EGb 761 as a single for 3 months did not produce insulin resistance in the non-diabetic or pre-diabetic subjects or exacerbate the disease in the T2DM subjects.

Intensive Insulin Treatment in Critically Ill Trauma Patients Normalizes Glucose by Reducing Endogenous Glucose Production

Critical illness is associated with insulin resistance and hyperglycemia. Intensive insulin treatment to normalize blood glucose during feeding has been shown to improve morbidity and mortality in patients in intensive care. The mechanisms behind the glucose-controlling effects of insulin in stress are not well understood. Six previously healthy, severely traumatized patients (injury severity score > 15) were studied early (24-48 h) after trauma. Endogenous glucose production (EGP) and whole-body glucose disposal (WGD) were measured (6,6-(2)H(2)-glucose) at basal, during total parenteral nutrition (TPN), and during TPN plus insulin to normalize blood glucose (TPN+I). Six matched volunteers served as controls. At basal and TPN, concentrations of glucose and insulin were higher in patients (P < 0.05). During TPN+I, insulin concentrations were 30-fold higher in patients. At basal, WGD and EGP were 30% higher in patients (P < 0.05). During TPN, EGP decreased in both groups but less in patients, resulting in 110% higher EGP than controls (P < 0.05). Normoglycemia coincided with reduced EGP, resulting in similar rates in both groups. WGD did not change during TPN or TPN+I and was not different between the groups. In conclusion, in healthy subjects, euglycemia is maintained during TPN at physiological insulin concentrations by a reduction of EGP, whereas WGD is maintained at basal levels. In traumatized patients, hyperglycemia is due to increased EGP. In contrast to controls, normalization of glucose concentration during TPN needs high insulin infusion rates and is accounted for by a reduction in EGP, whereas WGD is not increased.

Impaired Glucose Homeostasis in Mice Lacking the α1b-Adrenergic Receptor Subtype

To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.

Hepatic insulin resistance in obese non-diabetic subjects and in type 2 diabetic patients.

Obese non-diabetic patients are characterized by an extra-hepatic insulin resistance. Whether obese patients also have decreased hepatic insulin sensitivity remains controversial. To estimate their hepatic insulin sensitivity, we measured the rate of exogenous insulin infusion required to maintain mildly elevated glycemia in obese patients with type 2 diabetes, obese non-diabetic patients, and lean control subjects during constant infusions of somatostatin and physiological low-glucagon replacement infusions. To account for differences in insulin concentrations among the three groups of subjects, an additional protocol was also performed in healthy lean subjects with higher insulin infusion rates and exogenous dextrose infusion. The insulin infusion rate required to maintain glycemia at 8.5 mM was increased 4-fold in obese patients with type 2 diabetes and 1.5-fold in obese non-diabetic patients. The net endogenous glucose production (measured with 6,6-(2)H(2)-glucose) and total glucose output (measured with 2-(2)H(1)-glucose) were approximately 30% lower in the patients than in the lean subjects. Net endogenous glucose production and total glucose output were both markedly increased in both groups of obese patients compared with lean control subjects during hyperinsulinemia. Our data indicate that both obese non-diabetic and obese type 2 diabetic patients have a blunted suppressive action of insulin on glucose production, indicating hepatic and renal insulin resistance.

Insulin regulation of glucose transport and phosphorylation in skeletal muscle assessed by PET.

The current study examined in vivo insulin regulation of glucose transport and phosphorylation in skeletal muscle of healthy, lean volunteers. Positron emission tomography (PET) imaging and compartmental modeling of the time course of skeletal muscle uptake and utilization after a bolus injection of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) was performed during metabolic steady-state conditions at four rates of euglycemic insulin infusion. Leg glucose uptake (LGU) was determined by arteriovenous limb balance assessments. The metabolism of [(18)F]FDG strongly correlated with skeletal muscle LGU (r = 0.72, P < 0.01). On the basis of compartmental modeling, the fraction of glucose undergoing phosphorylation (PF) increased in a dose-responsive manner from 11% during basal conditions to 74% at the highest insulin infusion rate (P < 0.001). The PF and LGU were highly correlated (r = 0.73, P < 0.001). Insulin also increased the volume of distribution of nonphosphorylated [(18)F]FDG (P < 0.05). In step-wise regression analysis, the volume of distribution of nonphosphorylated [(18)F]FDG and the rate constant for glucose phosphorylation accounted for most of the variance in LGU (r = 0.91, P < 0.001). These findings indicate an important interaction between transport and phosphorylation in the control of insulin-stimulated glucose metabolism in skeletal muscle.

Measurement of interstitial insulin in human muscle.

Previous measurements in lymph and adipose tissue have indicated that interstitial insulin concentrations are approximately 40% lower than in plasma. Measurements of insulin in human muscle interstitial fluid have not been performed yet. We developed a new external reference technique for calibration of microdialysis catheters in situ. This technique allows correct assessments of interstitial peptide concentrations and was employed to estimate the insulin concentration in medial quadriceps femoris muscle in 11 individuals (age: 37 +/- 3 yr; body mass index: 25.2 +/- 1.2 kg/m2) during a two-step euglycemic hyperinsulinemic clamp. At steady-state insulin and glucose infusion, plasma glucose was 5.9 +/- 0.2 mmol/l, plasma insulin was 155 +/- 17 mU/l, and interstitial muscle insulin was 67 +/- 19 mU/l (n = 9; P < 0.01). At a higher insulin infusion rate, the steady-state plasma insulin concentration was 379 +/- 58 mU/l, and interstitial insulin concentration was 180 +/- 40 mU/l (P < 0.01). The data show for the first time that high physiological and supraphysiological plasma insulin levels give 30-50% lower interstitial concentrations of insulin in the muscle. The importance of capillary delivery as a rate-limiting step for the insulin effect is suggested.

Glucose metabolism and insulin sensitivity in Dahl hypertensive rats.

There is increasing recognition that hypertension is only one facet of a metabolic syndrome that represents a cluster of risk factors including insulin resistance evident during long-term development of cardiovascular disease. The objectives of the present study were to evaluate glucose metabolism and insulin sensitivity in the Dahl genetic salt-sensitive rat model of hypertension and to find out whether there is a correlation between high blood pressure, salt sensitivity and insulin sensitivity. The experiments were performed in Wistar and Dahl salt-resistant (DSR) and salt-sensitive (DSS) rats given a normal or salt-loaded (2% NaCl in the drinking water) diet for 2 months. Glucose turnover, metabolic clearance of glucose and insulin sensitivity were determined using the euglycemic clamp technique in anesthetized animals. Four different concentrations of insulin were used (2.1, 4.2, 8.4 and 16.8 mg/kg/min) with results showing that there were no significant differences in serum glucose and insulin levels, glucose utilization and clearance and insulin sensitivity between Wistar and DSR; these groups remained normotensive throughout the 2-month experiment. However, DSS rats, even on a normal diet, developed hypertension by the end of the experiment and consistent with their hypertensive condition, significantly decreased glucose utilization and clearance and decreased insulin sensitivity were observed. The changes were more marked at higher insulin infusion rates (8.4 and 16.8 mg/kg/min). These results demonstrate that DSS rats with fully developed hypertension were insulin resistant. In contrast, DSR rats remained normotensive despite sodium loading. Sodium loading significantly exaggerated the hypertensive state of DSS rats but did not further increase insulin resistance. The results from respective weanling rats showed that even at this early stage before development of hypertension, DSS rats already had significantly increased serum insulin suggesting insulin resistance. In conclusion, the present results suggest that DSR genetically hypertensive rats were insulin resistant although insulin resistance was unrelated to high blood pressure or NaCl intake.

Effect of salt-loading on blood pressure, insulin sensitivity and limb blood flow in normal subjects

1. The aim of this study was to determine the effects of high (220 mmol/day) and low (40 mmol/day) salt intake for 6 days on blood pressure, leg blood flow and insulin sensitivity in 18 healthy normotensive subjects. 2. Twenty-four-hour ambulatory blood pressure was measured at baseline, during salt-loading and salt-depletion. Insulin sensitivity was determined by a two-step euglycaemic-hyperinsulinaemic clamp (low and high insulin infusion rates: 40 and 600 m-unit.min-1.m-2 respectively) and leg blood flow by plethysmography. 3. Salt-loading resulted in changes in weight [change between salt-loading and salt-restriction: delta=+0.45 (S.D. +/-0.69) kg, P=0.015], plasma renin [delta=-11.5 (S.D.+/-12.9) micro-units/l, P=0.001] and urinary noradrenaline [delta=-8.6 (S.D. +/-18.7) nmol/mmol creatinine, P=0.05]. There were borderline significant increases in 24-h systolic blood pressure [delta=+5.8 (S. D.+/-14.2) mmHg, P=0.06] and plasma volume [delta=+0.29 (S.D.+/-0. 67) litres, P=0.08]. 4. Insulin sensitivity was similar in both salt states. Geometric mean metabolic clearance rate of low-dose insulin: low salt, 5.13 (S.D.x//1.35) dl/min; high salt, 4.94 (S.D.x//1.37) dl/min, P=1.0. Geometric mean metabolic clearance rate of high-dose insulin: low salt, 9.68 dl/min (S.D.x//1.30); high salt, 9.68 (S.D. x//1.27) dl/min, P=0.69. 5. Leg blood flow response to high-dose insulin on high salt increased significantly compared with low salt. Percentage change of blood flow on low salt, delta=+36.6 (S.D.+/-22. 9)% versus high salt, delta=+66.8 (S.D.+/-52.2)%, P=0.03. 6. There were no significant relationships between salt-related changes in limb blood flow and changes in insulin sensitivity at either insulin infusion rate. 7. We conclude that salt-loading, despite changing body weight, the renin-angiotensin-aldosterone system, urinary noradrenaline and the leg blood flow response to insulin, has no significant effect on insulin sensitivity. Salt-loading causes dissociated effects on insulin-induced vasodilatation and glucose disposal.

Preoperative oral carbohydrate administration reduces postoperative insulin resistance

Infusions of carbohydrates before surgery reduce postoperative insulin resistance. We investigated the effects of a carbohydrate drink, given shortly before surgery, on postoperative metabolism. Method:Insulin sensitivity, glucose turnover ([6,6, 2H2]-D-glucose) and substrate utilization were measured using hyperinsulinemic normoglycemic clamps and indirect calorimetry in two matched groups of patients before and after elective colorectal surgery. The drink group (n = 7) received 800 ml of an isoosmolar carbohydrate rich beverage the evening before the operation (100 g carbohydrates), as well as another 400 ml (50 g carbohydrates) 2 h before the initiation of anesthesia. The fasted group (n = 7) was operated after an overnight fast. Results:After surgery, energy expenditure increased in both groups. Endogenous glucose production was higher after surgery and the difference was significant during low insulin infusion rates in both groups (P < 0.05). The supressibility of endogenous glucose production by the two step insulin infusion was similar pre- and postoperatively in both groups. At the high insulin infusion rate postoperatively, whole body glucose disposal was more reduced in the fasted group (−49 ± 6% vs −26 ± 8%, P < 0.05 vs drink). Furthermore, during high insulin infusion rates, glucose oxidation decreased postoperatively only in the fasted group (P < 0.05) and postoperative levels of fat oxidation were greater in the fasted group (P < 0.05 vs drink). Only minor postoperative changes in cortisol and glucagon were found and no differences were found between the treatment groups. Conclusions:Patients given a carbohydrate drink shortly before elective colorectal surgery displayed less reduced insulin sensitivity after surgery as compared to patients who were operated after an overnight fast.

Interstitial muscle insulin and glucose levels in normal and insulin-resistant Zucker rats.

To study interstitial insulin and glucose concentrations, microdialysis was performed in the medial femoral muscles in normal SD rats as well as in insulin-resistant obese Zucker rats during a euglycemic insulin clamp. [14C]inulin was given (0.1 mCi/rat) as a constant subcutaneous infusion 24 h before the insulin clamp. Insulin infusion rates were 5-8 mU x kg(-1) x min(-1) (low rate) for 140 min and 10-20 mU x kg(-1) x min(-1) (high rate) for another 100 min. The relationship between insulin and [14C]inulin dialysate recoveries was evaluated in vivo and in vitro in plasma to calculate interstitial insulin concentration. Relative microdialysis recovery of interstitial insulin in vivo was 3.0 +/- 0.3% (mean +/- SE, n = 68). In normal SD rats, plasma and interstitial insulin concentrations were identical when plasma insulin was < or =250 mU/ml, whereas interstitial insulin was lower when plasma insulin was > or =350 mU/ml. Half-maximal glucose infusion rate was achieved in the presence of plasma and interstitial insulin concentrations of approximately 140 mU/ml, whereas maximal glucose disposal was seen at interstitial insulin concentrations of approximately 325 mU/ml, corresponding to approximately 500 mU/ml in plasma. In electrically stimulated and contracting (1 Hz) normal muscle with markedly increased blood flow, the dialysate insulin concentration was significantly higher at high rates, but not at low rates, of insulin infusion. In insulin-resistant obese Zucker rats, the interstitial insulin concentration was similar to that in plasma, even at pharmacological concentrations. The glucose infusion rate was significantly lower in the obese Zucker rats at both insulin infusion rates than in the lean animals. The glucose content in dialysates from skeletal muscle was equal in both obese and lean rats during the low insulin infusion rate. During the high insulin infusion rate, dialysate glucose concentrations decreased significantly in both groups but were significantly higher in the obese Zucker rats. The data suggest that transport of insulin and glucose diffusion across the capillary wall are rate limiting for insulin as well as for glucose metabolism in muscle in normal rats. This does not appear to be the case in the insulin-resistant obese Zucker rats, where the reduced insulin responsiveness in muscle is due to muscular cellular defects rather than an inhibited transcapillary delivery of insulin.

Effect of dietary sodium on insulin sensitivity in older, obese, sedentary hypertensives.

Increased dietary sodium intake has been associated with an increase in blood pressure as well as a decrease in insulin-mediated glucose disposal in young healthy adults. The purpose of this study was to determine whether dietary sodium intake is associated with changes in oral glucose tolerance, insulin sensitivity, and blood pressure in older, sedentary, overweight hypertensives. Eight older (70.0 +/- 1.4 years, mean +/- SEM), overweight (40.2 +/- 3.1% body fat), mildly hypertensive (151 +/- 8/82 +/- 2 mm Hg) patients with a fasting plasma glucose < 7.8 mmol/L were studied after 2 weeks on low (3 g/day) and 2 weeks on high (10 g/day) sodium diets. To examine carbohydrate metabolism we performed a 2 h oral glucose tolerance test and a two-dose (240 and 600 pmol/m2/min) hyperinsulinemic-euglycemic clamp at the end of each sodium diet. High sodium intake was associated with a significantly greater urinary sodium excretion (364 +/- 45 mmol/day v 112 +/- 21 mmol/day; P < .0001). The increase in dietary sodium from low to high did not result in significant differences in fasting plasma glucose (6.0 +/- 0.2 v 5.8 +/- 0.1 mmol/L, P = .20) or insulin (72.5 +/- 7.8 v 69.9 +/- 12.4 pmol/L, P = 0.71) levels or in the glucose (374.0 +/- 50.8 v 493.2 +/- 45.0 mmol/min/L, P = .12) and insulin (43,783 +/- 10,278 v 44,110 +/- 12,392 pmol/min/L, P = .96) areas determined during the oral glucose tolerance test. Similarly, there was no effect of dietary sodium on insulin-mediated glucose disposal at low (5.87 +/- 1.02 v 5.60 +/- 0.94 mg/kgLBM/min, P = .36) or high (12.15 +/- 1.49 v 11.91 +/- 1.49 mg/kgLBM/min, P = .64) insulin infusion rates. Our findings suggest that, in insulin resistant hypertensives, increased dietary sodium does not affect either glucose or insulin responses during an oral glucose tolerance test or glucose disposal during a hyperinsulinemic euglycemic clamp.