Constant Insulin Infusion Research Articles

The role of pre-pregnancy care for women with pregestational diabetes mellitus for improving maternal and perinatal outcomes

The occurrence of diabetes mellitus in women before pregnancy (pregestational diabetes mellitus can have various adverse consequences for the mother, fetus, child, and pregnancy. Pregnancy planning in women with pregestational diabetes mellitus significantly improves the outcomes of pregnancy and childbirth. The introduction of diabetes self-control skills, the use of human insulin and insulin analogues, the use of constant subcutaneous insulin infusion and family planning allows for optimal glycemic control in early pregnancy and reduces the incidence of fetal congenital anomalies and perinatal mortality. Lifestyle optimization, weight loss, taking adequate doses of folic acid, discontinuation of teratogenic medications, and quitting smoking are essential components of preconception care. Of significant clinical value is the training of women planning pregnancy at the Diabetes school, training in self-control and insulin therapy skills, consultation with an endocrinologist, an obstetrician-gynecologist, an ophthalmologist, a nephrologist, and a nutritionist.
 The aim of this study was to present current data on pre-pregnancy care in patients with pregestational diabetes mellitus and to show its possibilities in reducing the frequency of obstetric and perinatal complications. We analyzed 74 domestic and foreign literature sources using the following databases: PubMed, PubMed Central, Google Scholar, and UpToDate.

159-OR: Endocrine and Metabolic Counterregulation to Standardized Postprandial Hypoglycemia after Bariatric Surgery

Aim: To compare endocrine and metabolic counterregulation to postprandial hypoglycemia in patients with postbariatric hypoglycemia (PBH) after gastric bypass (GB) vs. surgical and non-surgical controls. Methods: Thirty-two adults (age 42.9±12.8 years, 13% male, BMI 28.2±4.3kg/m2) of 4 matched groups (PBH patients, GB, sleeve gastrectomy [SG] and non-surgical controls [CON]) ingested 15g glucose with subsequent induction of hypoglycemia (target 2.5mM) at t150-170 min using a constant insulin infusion with controller-guided iv dextrose adjustment. Primary outcome was mean glucagon during hypoglycemia (t150-170) . Further outcomes were responses of catecholamines, cortisol, growth hormone, pancreatic polypeptide (PP) , glucagon-like peptide 1, endogenous glucose production (EGP) and exogenous insulin. Values are shown as mean±SD. Results: Plasma glucose and insulin at t150-170 were 2.6±0.2mM and 891±382pM across all groups. Glucagon was significantly lower in all surgical groups (PBH: 12.0±8.2pM, GB: 13.4±5.7pM and SG: 11.0±6.8pM vs. CON: 23.0±6.2pM, p=0.005) . PP was significantly lower in PBH vs. CON (28.1±49.6pM vs. 146.0±93.5pM, p=0.01) . EGP did not differ significantly between groups, nor did any other hormones. Conclusion: Our results suggest diminished glucagon response to postprandial hypoglycemia after GB and SG compared to CON, with additionally lower PP values in PBH. Disclosure A.Tripyla: None. J.Zehetner: None. D.Giachino: None. S.Del favero: Research Support; Dexcom, Inc. A.Thomas: None. M.Thevis: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. L.Bally: None. D.Herzig: None. G.Reverter branchat: Employee; Fresenius Medical Care. J.Pavan: None. M.Schiavon: None. P.J.Eugster: None. E.Grouzmann: None. C.T.Nakas: None. S.Valérie: None. Funding Swiss National Science Foundation (PCEGP3_186978)

Automatic Regulation of Basal Insulin Infusion in a Personalized Insulin Therapy System

A method and a system for automatic regulation of the basal insulin administration rate for maintenance of glycemia in the target range are proposed. The method is based on proportional regulation of the infusion rate using feedback. It suspends the insulin delivery when the glucose level falls below a threshold value. According to the modeling results, the proposed method can be used to compensate hyperglycemia of different etiologies with reduction of the settling time in comparison with constant rate insulin infusion.

Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport

IntroductionInsulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.MethodsWe applied the pancreatic...

Sevoflurane Impairs Insulin Secretion and Tissue-Specific Glucose Uptake In Vivo.

The use of anaesthetics severely influences substrate metabolism. This poses challenges for patients in clinical settings and for the use of animals in diabetes research. Sevoflurane can affect regulation of glucose homoeostasis at several steps, but the tissue-specific response remains to be determined. The aim of the study was to investigate the pharmacological effect of sevoflurane anaesthesia on glucose homoeostasis during hyperinsulinaemic clamp conditions, the gold standard method for assessment of whole-body insulin sensitivity. Conscious mice (n = 6) and mice under sevoflurane anaesthesia (n = 8) underwent a hyperinsulinaemic clamp where constant infusion of insulin and donor blood was administered during variable glucose infusion to maintain isoglycaemia. 2-[1-14 C]-deoxy-D-glucose was infused to determine tissue-specific uptake of glucose in adipose tissue, heart, brain and skeletal muscle. Sevoflurane anaesthesia severely impaired insulin-stimulated whole-body glucose uptake demonstrated by a 50% lower glucose infusion rate (GIR). This was associated with decreased glucose uptake in brain, soleus, triceps and gastrocnemius muscles in sevoflurane-anaesthetized mice compared to conscious mice. Plasma-free fatty acids (FFA), a potent inducer of insulin resistance, increased by 42% in mice during sevoflurane anaesthesia. In addition, insulin secretion from pancreatic β-cell was lower in fasted, anaesthetized mice. Sevoflurane anaesthesia impairs insulin secretion, induces insulin resistance in mice and reduces glucose uptake in non-insulin-sensitive tissue like the brain. The underlying mechanisms may involve sevoflurane-induced mobilization of FFA.

Tissue IGF-I Measured by Microdialysis Reflects Body Glucose Utilization After rhIGF-I Injection in Type 1 Diabetes.

Type 1 diabetes is associated with portal insulin deficiency and disturbances in the GH-IGF axis including low circulating IGF-I and GH hypersecretion. Whether peripheral hyperinsulinemia and GH hypersecretion, which are relevant to the development of vascular complications, result in elevated tissue IGF-I remains unknown. The purpose of this study was to determine the relationship between whole-body glucose uptake and tissue IGF-I measured by microdialysis. This was a single-blind placebo-controlled crossover study. The setting was a tertiary pediatric endocrine referral center. The participants were seven young male adults with type 1 diabetes. After an overnight fast, a 6-h lasting euglycemic clamp was performed (constant insulin infusion at 0.5 mU/kg × minute and variable glucose infusion rate [GIR]) and a subcutaneous injection of recombinant human (rh) IGF-I (120 μg/kg) or saline was given after 2 hours. In parallel, tissue IGF-I levels were determined by microdialysis (md-IGF-I). md-IGF-I levels in muscle and subcutaneous fat, and GIR were determined. md-IGF-I levels were detectable but unchanged after saline. After rhIGF-I, muscle and subcutaneous fat md-IGF-I increased during the second and third hour and then reached a plateau up to 10-fold higher than baseline (P < .001). GIR was unchanged after saline, whereas it increased 2.5-fold concomitantly with the increase in md-IGF-I (P < .0001). In contrast, serum IGF-I was increased already at 30 minutes after rhIGF-I and reached a plateau 2-fold above baseline (P < .0001). We demonstrate that md-IGF-I measurements are valid and physiologically relevant by reflecting rhIGF-I-induced glucose uptake. Future studies should be conducted to elucidate the role of local tissue IGF-I in diabetic vascular complications.

Glucose predictability, blood capillary permeability, and glucose utilization rate in subcutaneous, skeletal muscle, and visceral fat tissues

This study suggests an approach for the comparison and evaluation of particular compartments with modest experimental setup costs. A glucose level prediction model was used to evaluate the compartment's glucose transport rate across the blood capillary membrane and the glucose utilization rate by the cells. The glucose levels of the blood, subcutaneous tissue, skeletal muscle tissue, and visceral fat were obtained in experiments conducted on hereditary hypertriglyceridemic rats. After the blood glucose level had undergone a rapid change, the experimenter attempted to reach a steady blood glucose level by manually correcting the glucose infusion rate and maintaining a constant insulin infusion rate. The interstitial fluid glucose levels of subcutaneous tissue, skeletal muscle tissue, and visceral fat were evaluated to determine the reaction delay compared with the change in the blood glucose level, the interstitial fluid glucose level predictability, the blood capillary permeability, the effect of the concentration gradient, and the glucose utilization rate. Based on these data, the glucose transport rate across the capillary membrane and the utilization rate in a particular tissue were determined. The rates obtained were successfully verified against positron emission tomography experiments. The subcutaneous tissue exhibits the lowest and the most predictable glucose utilization rate, whereas the skeletal muscle tissue has the greatest glucose utilization rate. In contrast, the visceral fat is the least predictable and has the shortest reaction delay compared with the change in the blood glucose level. The reaction delays obtained for the subcutaneous tissue and skeletal muscle tissue were found to be approximately equal using a metric based on the time required to reach half of the increase in the interstitial fluid glucose level.

Glucose metabolism during the early “flow phase” after burn injury

BackgroundBurn injury (BI) is associated with insulin resistance (IR) and hyperglycemia which complicate clinical management. We investigated the impact of BI on glucose metabolism in a rabbit model of BI using a combination of positron emission tomography (PET) and stable isotope studies under euglycemic insulin clamp (EIC) conditions. Materials and methodsTwelve male rabbits were subjected to either full-thickness BI (B) or sham burn. An EIC condition was established by constant infusion of insulin, concomitantly with a variable rate of dextrose infusion 3 d after treatment. PET imaging of the hind limbs was conducted to determine the rates of peripheral O2 and glucose utilization. Each animal also received a primed constant infusion of [6,6-2H2] glucose to determine endogenous glucose production. ResultsThe fasting blood glucose in the burned rabbits was higher than that in the sham group. Under EIC conditions, the sham burn group required more exogenous dextrose than the B group to maintain blood glucose at physiological levels (22.2 ± 2.6 versus 13.3 ± 2.9 mg/min, P < 0.05), indicating a state of IR. PET imaging demonstrated that the rates of O2 consumption and 18F 2-fluoro-2-deoxy-D-glucose utilization by skeletal muscle remained at similar levels in both groups. Hepatic gluconeogenesis determined by the stable isotope tracer study was found significantly increased in the B group. ConclusionsThese findings demonstrated that hyperglycemia and IR develop during the early “flow phase” after BI. Unsuppressed hepatic gluconeogenesis, but not peripheral skeletal muscular utilization of glucose, contributes to hyperglycemia at this stage.

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Type 2 diabetes is characterized by a defect in insulin action. The hyperinsulinemic-euglycemic clamp, or insulin clamp, is widely considered the "gold standard" method for assessing insulin action in vivo. During an insulin clamp, hyperinsulinemia is achieved by a constant insulin infusion. Euglycemia is maintained via a concomitant glucose infusion at a variable rate. This variable glucose infusion rate (GIR) is determined by measuring blood glucose at brief intervals throughout the experiment and adjusting the GIR accordingly. The GIR is indicative of whole-body insulin action, as mice with enhanced insulin action require a greater GIR. The insulin clamp can incorporate administration of isotopic 2[14C]deoxyglucose to assess tissue-specific glucose uptake and [3-3H]glucose to assess the ability of insulin to suppress the rate of endogenous glucose appearance (endoRa), a marker of hepatic glucose production, and to stimulate the rate of whole-body glucose disappearance (Rd). The miniaturization of the insulin clamp for use in genetic mouse models of metabolic disease has led to significant advances in diabetes research. Methods for performing insulin clamps vary between laboratories. It is important to note that the manner in which an insulin clamp is performed can significantly affect the results obtained. We have published a comprehensive assessment of different approaches to performing insulin clamps in conscious mice1 as well as an evaluation of the metabolic response of four commonly used inbred mouse strains using various clamp techniques2. Here we present a protocol for performing insulin clamps on conscious, unrestrained mice developed by the Vanderbilt Mouse Metabolic Phenotyping Center (MMPC; URL: www.mc.vanderbilt.edu/mmpc). This includes a description of the method for implanting catheters used during the insulin clamp. The protocol employed by the Vanderbilt MMPC utilizes a unique two-catheter system3. One catheter is inserted into the jugular vein for infusions. A second catheter is inserted into the carotid artery, which allows for blood sampling without the need to restrain or handle the mouse. This technique provides a significant advantage to the most common method for obtaining blood samples during insulin clamps which is to sample from the severed tip of the tail. Unlike this latter method, sampling from an arterial catheter is not stressful to the mouse1. We also describe methods for using isotopic tracer infusions to assess tissue-specific insulin action. We also provide guidelines for the appropriate presentation of results obtained from insulin clamps.

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Type 2 diabetes is characterized by a defect in insulin action. The hyperinsulinemic-euglycemic clamp, or insulin clamp, is widely considered the "gold standard" method for assessing insulin action in vivo. During an insulin clamp, hyperinsulinemia is achieved by a constant insulin infusion. Euglycemia is maintained via a concomitant glucose infusion at a variable rate. This variable glucose infusion rate (GIR) is determined by measuring blood glucose at brief intervals throughout the experiment and adjusting the GIR accordingly. The GIR is indicative of whole-body insulin action, as mice with enhanced insulin action require a greater GIR. The insulin clamp can incorporate administration of isotopic 2[14C]deoxyglucose to assess tissue-specific glucose uptake and [3-3H]glucose to assess the ability of insulin to suppress the rate of endogenous glucose appearance (endoRa), a marker of hepatic glucose production, and to stimulate the rate of whole-body glucose disappearance (Rd).The miniaturization of the insulin clamp for use in genetic mouse models of metabolic disease has led to significant advances in diabetes research. Methods for performing insulin clamps vary between laboratories. It is important to note that the manner in which an insulin clamp is performed can significantly affect the results obtained. We have published a comprehensive assessment of different approaches to performing insulin clamps in conscious mice1 as well as an evaluation of the metabolic response of four commonly used inbred mouse strains using various clamp techniques2. Here we present a protocol for performing insulin clamps on conscious, unrestrained mice developed by the Vanderbilt Mouse Metabolic Phenotyping Center (MMPC; URL: www.mc.vanderbilt.edu/mmpc). This includes a description of the method for implanting catheters used during the insulin clamp. The protocol employed by the Vanderbilt MMPC utilizes a unique two-catheter system3. One catheter is inserted into the jugular vein for infusions. A second catheter is inserted into the carotid artery, which allows for blood sampling without the need to restrain or handle the mouse. This technique provides a significant advantage to the most common method for obtaining blood samples during insulin clamps which is to sample from the severed tip of the tail. Unlike this latter method, sampling from an arterial catheter is not stressful to the mouse1. We also describe methods for using isotopic tracer infusions to assess tissue-specific insulin action. We also provide guidelines for the appropriate presentation of results obtained from insulin clamps.

Mice with AS160/TBC1D4-Thr649Ala Knockin Mutation Are Glucose Intolerant with Reduced Insulin Sensitivity and Altered GLUT4 Trafficking

SummaryAS160 has emerged as a key player in insulin-mediated glucose transport through controlling GLUT4 trafficking, which is thought to be regulated by insulin-stimulated phosphorylation of sites including the 14-3-3 binding phospho-Thr649 (equivalent to Thr642 in human AS160). To define physiological roles of AS160-Thr649 phosphorylation and 14-3-3 binding in glucose homeostasis, we substituted this residue by a nonphosphorylatable alanine by knockin mutation in mice. The mutant protein was expressed at normal levels, while insulin-stimulated AS160 binding to 14-3-3s was abolished in homozygous knockin mice. These animals displayed impaired glucose disposal and insulin sensitivity, which were associated with decreased glucose uptake in vivo. Insulin-stimulated glucose transport and cell surface GLUT4 content were reduced in isolated muscles, but not in adipocytes. These results provide genetic evidence that insulin-induced AS160-Thr649 phosphorylation and/or its binding to 14-3-3 play an important role in regulating whole-body glucose homeostasis, at least in part through regulating GLUT4 trafficking in muscle.

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.

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Use of a constant rate infusion of insulin for the treatment of hyperglycemic, hypernatremic, hyperosmolar syndrome in an alpaca cria

A 3-day-old 9.5-kg (21-lb) female alpaca cria was examined because of lethargy and anorexia. Physical examination revealed hyperthermia, muscle fasciculations, and tremors of the head. Seizures were also observed, which indicated CNS dysfunction. Hyperosmolar syndrome (HOS) was diagnosed on the basis of hyperglycemia, hypernatremia, azotemia, high plasma osmolarity, and metabolic acidosis. A constant rate infusion of regular insulin was administered with hypo-osmolar fluids to treat HOS, and blood glucose and sodium concentrations were successfully lowered. Neurologic deficits resolved with treatment, and the cria was discharged 11 days after admission. Administration of insulin as a bolus in addition to hypo-osmolar fluids has been advocated in the management of neonatal camelids with HOS. Administration of regular insulin via a constant rate IV infusion was used to successfully manage a neonatal camelid with HOS. This form of insulin administration may allow more control of glucose kinetics in these patients.

Simple modeling allows prediction of steady-state glucose disposal rate from early data in hyperinsulinemic glucose clamps

After a constant insulin infusion is initiated, determination of steady-state conditions for glucose infusion rates (GIR) typically requires >or=3 h. The glucose infusion follows a simple time-dependent rise, reaching a plateau at steady state. We hypothesized that nonlinear fitting of abbreviated data sets consisting of only the early portion of the clamp study can provide accurate estimates of steady-state GIR. Data sets from two independent laboratories were used to develop and validate this approach. Accuracy of the predicted steady-state GDR was assessed using regression analysis and Altman-Bland plots, and precision was compared by applying a calibration model. In the development data set (n = 88 glucose clamp studies), fitting the full data set with a simple monoexponential model predicted reference GDR values with good accuracy (difference between the 2 methods -0.37 mg x kg(-1) x min(-1)) and precision [root mean square error (RMSE) = 1.11], validating the modeling procedure. Fitting data from the first 180 or 120 min predicted final GDRs with comparable accuracy but with progressively reduced precision [fitGDR-180 RMSE = 1.27 (P = NS vs. fitGDR-full); fitGDR-120 RMSE = 1.56 (P < 0.001)]. Similar results were obtained with the validation data set (n = 183 glucose clamp studies), confirming the generalizability of this approach. The modeling approach also derives kinetic parameters that are not available from standard approaches to clamp data analysis. We conclude that fitting a monoexponential curve to abbreviated clamp data produces steady-state GDR values that accurately predict the GDR values obtained from the full data sets, albeit with reduced precision. This approach may help reduce the resources required for undertaking clamp studies.

Acute Suppression of Circulating sCD40L During Hyperglycemia and Euglycemic-Hyperinsulinemia in Healthy Young Males

sCD40L is a proatherogenic cytokine, part of the tumor necrosis factor (TNF) superfamily and consistently associated with obesity, diabetes, and increased cardiovascular risk. Although the role of sCD40L in the...

Effect of Experimentally Induced Hypoglycemia and Different Insulin Levels on Feelings of Hunger in Type 1 Diabetic Patients

This study investigates the impacts of experimentally induced hypoglycemia and different insulin infusion rates on feelings of hunger. Blood glucose and insulin levels were manipulated by hyperinsulinemic glucose clamp technique. Participants were 16 patients with type 1 diabetes (age 36.2+/-11.7 yrs, diabetes duration 9.0+/-6.3 yrs, HbA1c 8.2+/-2.0%). One group (n=8) received moderate, constant insulin infusion (0.8 microU/kg/min), whereas the insulin infusion was doubled in the other group (1.6 microU/kg/min). Blood glucose was lowered stepwise from euglycemia (5.6 mmol/l) to moderate hypoglycemia (2.5 mmol/l). As expected, there was a significant effect of hypoglycemia on feelings of hunger (F (3, 42)=41.7, p<0.01). But during high insulin infusion, feelings of hunger were significantly less intense than during moderate insulin infusion (F (1, 14)=7.2, p=0.02). Peripheral insulin levels seem to be associated with the intensity of feelings of hunger.

Glucagon chronically impairs hepatic and muscle glucose disposal

Defects in insulin secretion and/or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support (NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia (approximately 120 mg/dl). On day 3 of NS, animals received a constant low infusion of insulin (0.4 mU.kg-1.min-1) and either no glucagon (CONT), basal glucagon (0.7 ng.kg-1.min-1; BasG), or elevated glucagon (2.4 ng.kg-1.min-1; HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group (HiG+I) received elevated insulin (1 mU.kg-1.min-1) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10+/-2, 9+/-1, 7+/-1, and 24+/-4 microU/ml, and 24+/-5, 39+/-3, 80+/-11, and 79+/-5 pg/ml, CONT, BasG, HiG, and HiG+I, respectively. Glucagon infusion decreased the glucose requirements (9.3+/-0.1, 4.6+/-1.2, 0.9+/-0.4, and 11.3+/-1.0 mg.kg-1.min-1). Glucose uptake by both hepatic (5.1+/-0.4, 1.7+/-0.9, -1.0+/-0.4, and 1.2+/-0.4 mg.kg-1.min-1) and nonhepatic (4.2+/-0.3, 2.9+/-0.7, 1.9+/-0.3, and 10.2+/-1.0 mg.kg-1.min-1) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.

The effect of manipulation of basal pulsatile insulin on insulin action in Type 2 diabetes

Disordered insulin pulsatility is associated with insulin resistant states including Type 2 diabetes. However, whether abnormal basal insulin pulses play a role in the pathogenesis of insulin resistance or are simply an associated feature remains undetermined. We investigated this relationship further by studying the effect of overnight (10 h) pulsatile insulin infusion on subsequent insulin sensitivity. We studied 17 Type 2 diabetic patients who underwent one of two protocols. In protocol A (10 patients) on two separate nights we infused insulin 0.1 mU/kg/min either in a constant infusion or in pulses every 13 min. Octreotide (0.43 microg/kg/h) was given to suppress endogenous insulin secretion and physiological replacement of glucagon (30 ng/kg/h) administered. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp (2 mU/kg/min) next morning. In protocol B (seven patients), we employed the same experimental procedure but used a basal insulin infusion rate of 0.09 mU/kg/min in 7-min or 13-min pulses. Appropriate pulse patterns were confirmed in each protocol. In protocol A, after overnight infusions, glucose infusion rates required to maintain euglycaemia at steady state hyperinsulinaemia were similar (33.9 +/- 5.2 vs. 31.2 +/- 4.1 micromol/kg/min; P = NS). In protocol B, after overnight infusions the glucose infusion rates required during hyperinsulinaemia were significantly lower during 7-min pulses (39.9 +/- 5.7 vs. 44.7 +/- 5.6 micromol/kg/min; P < 0.05). There was no demonstrable priming effect derived from overnight pulsatile insulin compared with constant insulin infusion on subsequent insulin sensitivity in Type 2 diabetic subjects. The failure of 7-min pulses to exhibit an advantageous effect over 13-min pulses raises questions about the natural frequency of basal insulin pulses and their biological effect.

My Love Affair with Insulin: JBC Centennial 1905-2005 100 Years of Biochemistry and Molecular Biology

My Love Affair with Insulin: JBC Centennial 1905-2005 100 Years of Biochemistry and Molecular Biology