Increment In Insulin Concentration Research Articles

Impaired Early Insulin Response to Glucose Load Predicts Episodic Memory Decline: A 10-Year Population-Based Cohort Follow-Up of 45-74-Year-Old Men and Women.

Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer's disease. To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45-74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001-2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE&z.epsi;4 genotype, vascular risk factors including diabetes, and depressive symptoms. A lower early insulin response to glucose load predicted lower performance (β: 0.21, p = 0.03) and greater decline (β: 0.19, p = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values≥0.13). Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

Insulin secretory function in Type 2 diabetes: Does it matter how you measure it?

The following estimates of insulin secretory function have been used widely to evaluate the role of pancreatic β-cells in the pathogenesis and treatment of patients with type 2 diabetes (2DM): (i) Homeostatic Model Assessment (HOMA)-β, a calculation based on fasting plasma glucose and insulin concentrations; (ii) post-glucose acute insulin response (AIRg), the increment in insulin concentration measured in the 5 min after intravenous glucose; and (iii) ΔI/ΔG, the ratio of the increment in plasma insulin concentration (I)/increment in plasma glucose concentration (G) 30 min after the oral administration of 75 g glucose. Experiments based on these approaches have led to a widely held point of view that that the natural history of 2DM is characterized by a progressive increase in the magnitude of hyperglycemia, secondary to an inexorable decline in pancreatic β-cell function: the greater the increase in plasma glucose concentration, the greater the impairment of the ability of the pancreas to secrete insulin. In the present review, theoretical questions are raised as to the physiological validity of these estimates of insulin secretory function and experimental data are presented demonstrating that hourly measurements of plasma insulin and glucose concentrations in response to mixed meals throughout an 8-h day lead to a very different point of view. Studies are also reviewed that question the 'inexorability' of the changes in insulin secretory function that have been reported. It is concluded that it may be time to challenge current conventional wisdom as to the role of the β-cell in the natural history of 2DM.

The multiphasic profile of free fatty acids during the intravenous glucose tolerance test is unresponsive to exogenous insulin

As small increments in insulin concentration profoundly affect lipolysis, our goal was to describe the free fatty acid (FFA) profile during the frequently sampled intravenous glucose tolerance test (FSIGT) and determine if both endogenous and exogenous insulin influenced the FFA profile. Thirteen subjects had both a glucose-only (GO-FSIGT) and insulin-modified FSIGT (IM-FSIGT). Both protocols were of 6 hours duration. At baseline an intravenous glucose bolus (0.3 g/kg) was given. In the IM-FSIGT, insulin was infused from 20 to 25 minutes (4 mU/kg · min). Six additional subjects had both an IM-FSIGT and a normal saline study (NS-Study). For the NS-Study, normal saline solution was infused instead of glucose and insulin. Fasting glucose, insulin, FFA and epinephrine concentrations were similar for all tests. Endogenous insulin peaked at 4 ± 1 minute in both FSIGTs. The mean calculated peak time of exogenous insulin in the IM-FSIGT was 26 ± 1 minute. Glucose concentrations were lower and epinephrine concentrations higher in the IM-FSIGT versus GO-FSIGT. During the FSIGTs, the FFA time course revealed four distinct phases, which did not differ between protocols. In phase I (0 to 11 minutes), FFA levels remained near basal (491 ± 183 μmol/L); in phase II (11 to 79 minutes), FFA levels declined achieving a nadir of 139 ± 63 μmol/L; in phase III (79 to 188 minutes), FFA levels rose linearly and reattained basal levels; and in phase IV (188 to 360 minutes), FFA levels rose above basal and plateaued at 732 ± 214 μmol/L ( P < .001). In the NS-Study, FFA levels remained near baseline (388 ± 118 mEq/L) until 180 minutes and then trended upward to 618 ± 258 μmol/L at 360 minutes. FFA concentrations from 180 to 360 minutes did not differ in the IM-FSIGT versus NS-Study. As the 4 FFA phases did not differ between protocols, the insulin effect on FFA levels in the FSIGT can be attributed to endogenous insulin. But the similarity in FFA levels from 180 to 360 minutes in the IM-FSIGT and NS-Study suggests diurnal variation and not a dynamic related to insulin or the FSIGT protocol is responsible for the final suprabasal FFA plateau.

Relation between insulin kinetics and insulin sensitivity in pregnancy.

Different time-concentration profiles of plasma insulin following insulin modification of a frequently sampled intravenous glucose-tolerance-test (FSIVGTT) were observed in a study investigating maternal metabolism and fetal macrosomia. We aimed to investigate whether these differences were related to the volume of distribution of insulin, insulin clearance, or both. Forty-four women were studied between 33 and 35 weeks' gestation using an insulin-modified FSIVGTT. Specific insulin was assayed with an enzyme-linked immunosorbent assay. Insulin sensitivity was calculated using the minimal model and the homeostasis model assessment (HOMA). The volume of distribution and clearance of insulin were calculated from measurements between 2 and 155 min after insulin modification using a one-compartment model. In accordance with the method for deriving the volume of distribution, there was a significant negative correlation between the increment in insulin concentration and the volume of distribution (rho=-0.92, P<0.0001). The insulin increment was also related negatively to the clearance of insulin (rho=-0.88, P<0.0001). There was a significant correlation between the volume of distribution and both the insulin sensitivity index (rho=0.56, P<0.0001) and HOMA-%S (rho=0.30, P=0.048), and between the clearance of insulin and both the insulin sensitivity index (rho=0.83, P<0.0001)) and HOMA-%S (rho=0.34, P=0.025). The different time-concentration profiles of plasma insulin resulted from differences in the volume of distribution and clearance of insulin. There was a correlation between insulin kinetics and the insulin sensitivity index. Further research is required to investigate possible mechanisms by which insulin kinetics may be related to insulin sensitivity.

Understanding Oral Glucose Tolerance: Comparison of Glucose or Insulin Measurements During the Oral Glucose Tolerance Test with Specific Measurements of Insulin Resistance and Insulin Secretion

The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r = 0.61, p < 0.001) but not insulin resistance (r = -0.05, p > 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = -0.53, p < 0.001) and insulin secretion (r = 0.07, p > 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r = -0.57, p < 0.001) but not insulin secretion (r = 0.01, p > 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

Effects of insulin at two dose levels on gluconeogenesis from alanine in fasting man

We have determined the effect of insulin infused at 1 and 5 mU/kg/min on gluconeogenesis from alanine in 48-hr fasted men. The conversion of alanine to glucose was measured by the arterial-hepatic venous catheterization technique combined with the infusion of 14C-alanine. During insulin infusion, euglycemia was maintained by variable glucose infusion. When insulin was infused at 1 mU/kg/min the net splanchnic production of 14C-glucose was suppressed by 80% but glucagon infused at the end of the study resulted in substantial release of 14C-glucose from the liver suggesting marked accumulation of labeled glucose in glycogen. When insulin was infused at 5 mU/kg/min the splanchnic release of 14C-glucose was also markedly suppressed but in contrast to the lower insulin dose very little labeled glucose accumulated in glycogen. Neither the high nor the low dose insulin infusion had any effect on net splanchnic alanine uptake and plasma glucagon levels fell by 35% in both protocols. These data demonstrate that in 48-hr fasted man, (1) a small increment in insulin concentration will suppress glucose production but mostly by diverting the newly formed glucose into glycogen; (2) at higher concentrations, insulin will inhibit glucose production mainly by suppressing gluconeogenesis; and (3) this insulin-induced suppression of gluconeogenesis is due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine.

Insulin, glucagon, and somatostatin in normal physiology and diabetes mellitus.

Studies are reviewed in which the roles of insulin and glucagon in normal physiology and in diabetes are examined. In normal man, glucose ingestion is accompanied by a rise in insulin and fall in glucagon and is primarily disposed of in the liver, an organ sensitive to both hormones. However, infusions of glucagon in physiologic amounts indicate that insulin secretion rather than glucagon inhibition is the primary factor determining glucose disposal. Furthermore, minor elevations in blood glucose elicit increments in insulin concentration and inhibition of hepatic glucose output in the absence of changes in plasma glucagon. The primary physiologic role of glucagon is to prevent the hypoglycemia that would otherwise accompany noncarbohydrate (protein)-mediated insulin secretion. In diabetic as well as normal patients the stimulatory effect of glucagon on hepatic glucose production is evanescent. Increases in glucagon or changes in the I/G ratio can bring about deterioration in glucose tolerance or in diabetic control only so long as absolute insulin deficiency is present or pharmacologic elevations in glucagon are produced. After somatostatin administration, prolonged hypoinsulinemia in normal subjects is observed to result in fasting hyperglycemia in the absence of basal glucagon secretion. In diabetic patients the improvement in postprandial hyperglycemia produced by somatostatin can be accounted for by its inhibitory action on carbohydrate absorption in the gastrointestinal tract. It is concluded that insulin deficiency is the primary pathophysiologic disturbance in diabetes. While glocagon may worsen the consequences of insulin lack, it is neither sufficient nor necessary for the development of diabetes.

Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusions in dogs.

The suppressive effect of insulin on hepatic glucose production is generally recognized. Though it is well established that this effect is at least partially due to inhibition of glycogenolysis, controversy still exists about insulin's effect on gluconeogenesis. The present study was undertaken to determine whether insulin could affect gluconeogenesis from alanine in the intact dog and to compare the effect of insulin on glycogenolysis and gluconeogenesis. In anesthetized dogs fasted overnight, blood samples were drawn simultaneously from a femoral artery and hepatic vein. Alanine-U-14C, 10 mu Ci./kg., was infused over 110 minutes. A constant insulin infusion at either 1 or 5 mU./kg./min. was begun at 50 minutes, and blood glucose concentration was maintained by a variable glucose infusion. When insulin was infused at 1 mU./kg./min., resulting in plasma immunoreactive insulin (IRI) levels of 73 +/- 10 muU./ml., the net splanchnic glucose production (NSGP) was suppressed from 2.7 +/- 2 mg./kg./min. to virtually zero. In constrast, this small increment in insulin concentration had no demonstrable effect on the net splanchnic uptake of alanine or on the conversion of plasma alanine to glucose (7.9 +/- 0.3 mu mol/min.). Insulin infused at 5 mU./kg./min. resulted in IRI levels of 240 +/- 25 muU./ml. This higher insulin concentration was associated with a marked suppression of both the NSGP (100 per cent) and the conversion of plasma alanine to glucose (90 per cent) but did not affect the extraction of alanine by the splanchnic bed. Doses of both 1 and 5 mU./kg./min. were associated with a 35 per cent fall in immunoreactive glucagon levels. These data demonstrate that (1) glycogenolysis is more sensitive than gluconeogenesis to the inhibitory effect of small increments in insulin concentrations, (2) gluconeogenesis could be suppressed by insulin but only at higher insulin concentrations, (3) this suppression of gluconeogenesis from alanine by insulin was due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine, and finally, (4) that insulin can suppress glucagon in the absence of hyperglycemia.

The effect of fasting and glucose load on insulin secretion and the Staub-Traugott phenomenon in pigs.

SUMMARY Pigs were fasted for 18, 39, or 72 h; they were then given two glucose infusions, the second infusion 40 min after the first. Either 0·15, 0·30 or 0·75 g glucose/kg were given at each infusion. Plasma glucose, free fatty acids, insulin and 3-hydroxybutyrate concentrations were measured. The rate of glucose removal Kt was calculated after the first infusions, (Kt1), and after the second infusion (Kt2). When food was withheld the peak insulin concentration decreased in response to glucose but lack of food only affected the mean increase in insulin concentration when 0·75 g glucose/kg was given. The value of Kt1 decreased as the period without food increased and additions of insulin did not affect the difference in Kt1 between animals fasted for 18 h and those fasted for 72 h. Plasma insulin concentration was closely related to the rate of glucose removal; the correlation coefficient (r) for maximum rate of glucose removal versus maximum insulin concentration was 0·9; and that for mean rate of glucose removal versus mean increment in insulin concentration was 0·84. It is suggested that insulin does not itself determine the rate of glucose removal but is secreted in response to the amount of glucose removed. In the pig, the Staub—Traugott phenomenon was found to occur only under special circumstances. The relationship between Kt1 and Kt2 depended on the amount of glucose infused and the time during which food was withheld. Kt2 ranged from smaller than—through the same as—to greater than Kt1. The concentrations of free fatty acids, ketones or insulin did not explain the differences.

Diluents for insulin standards in immunoassay of insulin in undiluted ovine plasma by a double antibody technique.

Several methods are now available for the immunoassay of insulin in plasma. Of these, the double antibody technique of Hales & Randle (1963) is especially convenient. However, in studies of plasma insulin concentrations in the sheep with method C of Hales & Randle (1963), plasma samples assayed undiluted consistently yielded higher values than the same plasma samples assayed after 1:4 dilution with buffer B of Hales & Randle (1963). Addition of ovine insulin (0–200μ-u./ml.) to ovine plasma showed that the sensitivity of the assay was greater in undiluted plasma than in buffer, the decrease in antibody-bound labelled insulin for a given increment in insulin concentration being greater in the plasma system. Addition of 0·01 m-EDTA (Morgan, Sorenson & Lazarow, 1964; Sheldon & Taylor, 1965) did not eliminate this discrepancy. Insulin standards in buffer did not appear to provide a suitable baseline for assay of insulin in undiluted ovine plasma.