Hepatic Balances of Glucose and Insulin in Response to Physiological Increments of Endogenous Insulin during Glucose Infusions in Dogs.

Abstract. Hepatic glucose uptake was measured in dogs in relation to physiological increments of plasma insulin levels under steady state conditions. Endogenous insulin secretion was stimulated by the infusion of small glucose loads, achieving normoglycaemia or mild hyperglycaemia. The measurement of hepatic arterial and portal venous blood flows allowed calculation of the relationships between net hepatic balances of insulin and glucose, the magnitude of insulin extraction by the liver and the hepatic sensitivity to physiological levels of insulin. During normoglycaemia, small glucose loads (2 and 4. 5 mg/min. kg) reduced hepatic glucose output without a concomitant increase of the estimated total glucose utilization. No changes in arterial or hepatic venous plasma insulin levels occurred. Portal venous plasma insulin alone rose under the influence of the glucose stimulus. In the presence of hyper-glycaemia, the liver further reduced its glucose output. Infusions of 11. 3 mg/min. kg glucose resulted in reversal of hepatic glucose output to a net uptake of glucose. However, due to the large amounts of insulin emerging from the liver, peripheral tissue glucose utilization was significantly increased. A strong inverse correlation existed between arterial glucose concentration and hepatic glucose output as well as between portal venous plasma insulin level and hepatic glucose output. The net hepatic balance of insulin was promptly raised in response to the glucose perfusions, even when normoglycaemia was maintained. A highly significant, inverse correlation was demonstrated between net hepatic balance of insulin (i. e. net uptake of insulin by the liver) and hepatic glucose output. Hepatic insulin extraction ratio and hepatic plasma insulin clearance increased during glucose administration but no evident relationship to portal venous plasma insulin levels was found. These data suggest that insulin rather than glucose is the primary agent responsible for the reversal of the hepatic gradient of glucose in vivo.     

The Glucose-Induced Gastrointestinal Stimulation of Insulin Secretion in Man: Relation to Age and to Gastrin Release

Abstract. An oral 50 g glucose tolerance test and a simple intravenous glucose infusion test were performed in 20 young (20–32 years), 20 middle-aged (42–55 years), and 20 old (65–81 years) normal subjects. Blood glucose, serum insulin, and serum gastrin concentrations were measured during all tests. The intravenous glucose infusion duplicated the oral blood glucose curve in young, middle-aged, and half of the old subjects. In the remaining old subjects the intravenous blood glucose curve was below the oral blood glucose curve. Glucose and insulin concentrations were of similar magnitude in all groups, but maximum concentrations were reached later in the old subjects. Glucose per os induced a rapid rise in serum gastrin concentrations of the order of 10 pmol/1 and a subsequent decrease of about 20 pmol/1 in all groups. The intravenous glucose infusion induced no significant changes in serum gastrin concentrations. The non-glycaemic (i. e. enteral) stimulation of insulin secretion was expressed as the difference between the integrated incremental areas of the oral and intravenous insulin curves in subjects with identical glucose curves during the two tests. This stimulation was of similar magnitude in all age groups, and it was not correlated to variations in gastrin concentrations. However, in the young subjects the enteral stimulation was greater during the first 30 minutes and smaller during the two last hours when compared to the old subjects.
The results suggest that: 1. A simple intravenous glucose infusion test can be used to copy the oral blood glucose curve. 2. The size of the enteral stimulation of insulin secretion during the whole test is independent of age. 3. The action of the glucose-induced enteral stimulation is delayed with age, and closely linked to the dynamics of the glycaemic stimulus. 4. The glucose-induced gastrin release is probably too small to affect insulin secretion significantly.     

Plasma Insulin Responses to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects

The plasma insulin responses of normal weight and obese, diabetic, and nondiabetic subjects to intravenous glucose was only 30-40% of that seen after oral glucose, indicating that alimentary mechanism(s) in addition to the arterial blood sugar concentration regulate insulin secretion. Observations made in subjects with diverted portal circulation indicate that the alimentary insulinogenic mechanism is located in the intestinal tract. The insulinogenic potency of the alimentary and glycemic stimuli expressed in terms of insulin secretion per gram of glucose were remarkably similar within each group of individuals. Between these groups, however, there were considerable differences. Obesity, with or without associated diabetes, was associated with a true hypersecretory responsiveness, whereas diabetes was characterized, with or without obesity, by a marked impairment in insulin secretion. The experimental design used in these studies permitted quantitation of the magnitude of the glycemic component of an oral glucose load. As a consequence of impaired insulin secretion, a greater than normal proportion of the oral glucose load escapes initial hepatic extraction in the maturity-onset diabetic and enters the peripheral circulation. Therefore, in the noninsulin-requiring maturity-onset diabetic, the glycemic insulinogenic stimulus for a given oral glucose load is significantly greater than in normal subjects and accounts for the excessive plasma insulin responses observed late in the course of an oral glucose tolerance test.     

Peripheral Glucose Uptake in Relation to Physiological Levels of Plasma and Lymph Insulin

Abstract. The effects of physiological increments of plasma immunoreactive insulin upon tissue glucose uptake, tissue insulin uptake and lymph insulin levels were studied in the hind-limb (65% muscle, 27% skin and subcutaneous fat) of 38 anaesthetized dogs.
During intravenous glucose tolerance tests, the tissue glucose uptake remained within baseline values, whereas the net rates of glucose utilization and the concentrations of arterial plasma insulin increased as the load of glucose injected was raised. Significant amounts of endogenous insulin were cleared from plasma but were not recovered in lymph.
No glucose response was observed in the hind-limb tissues during intra-arterial infusions of exogenous insulin in conditions of strict normoglycaemia and constant blood flow. The infusions of insulin were designed to simulate the levels of endogenous hormone achieved in plasma during the glucose tolerance tests. Again, a high percentage of the injected insulin was fixed to the hind-limb tissues with no detectable rise of leg-lymph levels. At higher plasma insulin concentrations, both tissue glucose uptake and lymph insulin levels were increased.
The results show that the effect of plasma insulin on glucose uptake by muscle and fat in vivo is a threshold phenomenon. From the present knowledge of the physiology of lymph formation, the threshold phenomenon could largely be accounted for by insulin adsorption to the blood capillary walls.     

Iron Excess, Early Glucose Intolerance and Impaired Insulin Secretion in Idiopathic Haemochromatosis

Abstract. The relationship between iron storage and glucose metabolism was studied in 21 relatives of 4 patients with idiopathic haemochromatosis and in 10 healthy control subjects. In all individuals, plasma iron and iron binding capacity were measured and liver function was assessed. In addition, intravenous and oral glucose tolerance tests (IVGTT, OGTT), as well as tolbutamide (TTT) and insulin tolerance tests (ITT), were performed. Serum insulin (IRI) was measured. Liver biopsies were performed on the 21 relatives only.
In the relatives of patients with haemochromatosis, glucose tolerance was impaired and insulin secretion in response to hyperglycaemia diminished and/or delayed. Glucose intolerance increased with age but did not depend on abnormal liver function or excessive iron storage. Insulin release in response to tolbutamide was normal and insulin tolerance test failed to reveal insulin resistance.
The results suggest that:
1. There is an early glucose intolerance in healthy relatives of patients suffering from idiopathic haemochromatosis.
2. The glucose intolerance seems unrelated to measurable anomalies in iron metabolism.
3. The delayed insulin secretion in response to glucose resembles that observed in common maturity-onset diabetes mellitus.
4. The results obtained are compatible with the hypothesis that haemochromatosis and diabetes mellitus might be two distinct but genetically linked entities.     

Effects of Burn Injury on Insulin Secretion and on Sensitivity to Insulin in the Rat in vivo

Abstract. Both insulin resistance and impairment of insulin secretion are know to occur in man after injury. The relative importance of these effects was studied in rats 2 h after a non-lethal 20 % dorsal scald. No impairment of insulin secretion was found after this injury. Concentrations of both blood glucose and plasma insulin were elevated in scalded rats. Scalded rats responded to intravenous glucose injection (1. 0 g/kg) with a further rise in plasma insulin concentration, which remained normal for the prevailing blood glucose concentration. However, marked impairment of glucose tolerance was observed, indicating the presence of insulin resistance. After intravenous insulin injection (1. 0 U/kg) the initial rate coefficient for fall of blood glucose concentration was significantly lower (p < 0–02) in scalded (mean 3. 9 % min. ^-1) than in control rats (mean 6–3 % min. ^-1). The minimum in blood glucose concentration after insulin injection was reached at 10 min. in control rats, but not until 60 min. after injection in scalded rats. This difference was due to a delay in compensation for the hypoglycaemia in the scalded rats, since the rate of disappearance of insulin measured by injection of a tracer of 25i-labelled bovine insulin was not decreased after this injury. It was concluded that the impairment of glucose utilization in scalded rats (Heath and Corney, 1973) is due to decreased sensitivity to insulin rather than to suppression of insulin release.     

The Regulation of Splanchnic Glucose Production in Subjects with Low Insulin Response – a Compensatory Mechanism in Prediabetes?

Abstract. Splanchnic exchange of glucose, pyruvate, lactate, glycerol and individual amino acids was measured in 22 healthy non-obese men with normal glucose tolerance. Ten of the subjects had a diminished insulin response to glucose infusion and formed the group of low insulin responders. Basal insulin levels were significantly reduced in the latter group. In spite of this, the splanchnic glucose output was 45 per cent lower than in the controls. During the infusion of 2 mg glucose/kg/ min. for 45 min., a significant elevation of the arterial insulin concentration was observed only in the control group. However, splanchnic glucose output decreased more rapidly and to a greater extent in the low insulin responders despite significantly reduced insulin levels. The uptake of gluconeogenic precursors was similar in both groups. No differences were noted in the arterial glucagon levels. These findings are taken to indicate that hepatic sensitivity to endogenous insulin is augmented in low insulin responders, thereby providing a mechanism for maintaining normal glucose tolerance in the presence of subnormal insulin secretion.     

The glucose-induced gastrointestinal stimulation of insulin secretion in man: relation to age and to gastrin release.

An oral 50 g glucose tolerance test and a simple intravenous glucose infusion test were performed in 20 young (20 - 32 years), 20 middle-aged (42 -55 years), and 20 old (65 - 81 years) normal subjects. Blood glucose, serum insulin, and serum gastrin concentrations were measured during all tests. The intravenous glucose infusion duplicated the oral blood glucose curve in young, middle-aged, and half of the old subjects. In the remaining old subjects the intravenous blood glucose curve was below the oral blood glucose curve. Glucose and insulin concentrations were of similar magnitude in all groups, but maximum concentrations were reached later in the old subjects. Glucose per os induced a rapid rise in serum gastrin concentrations of the order of 10 pmol/1 and a subsequent decrease of about 20 pmol/1 in all groups. The intravenous glucose infusion induced no significant changes in serum gastrin concentrations. The non-glycaemic (i.e. enteral) stimulation of insulin secretion was expressed as the difference between the integrated incremental areas of the oral and intravenous insulin curves in subjects with identical glucose curves during the two tests. This stimulation was of similar magnitude in all age groups, and it was not correlated to variations in gastrin concentrations. However, in the young subjects the enteral stimulation was greater during the first 30 minutes and smaller during the two last hours when compared to the old subjects. The results suggest that: 1. A simple intravenous glucose infusion test can be used to copy the oral blood glucose curve. 2. The size of the enteral stimulation of insulin secretion during the whole test is independetn of age. 3. The action of the glucose-induced enteral stimulation is delayed with age, and closely linked to the dynamics of the glycaemic stimulus. 4. The glucose-induced gastrin release is probably too small to affect insulin secretion significantly.     

Insulin Metabolism,Insulin Sensitivity and Hormonal Responses to Insulin Infusion in Patients Taking Oral Contraceptive Steroids

Abstract. The metabolism of unlabelled human monocomponent insulin was studied in a group of six patients being treated with combined oestrogen-progestogen oral contraceptives (OC) and compared with a group of ten normal subjects. The parameters of insulin metabolism were determined by a priming dose - continuous infusion technique which enabled measurements of metabolic clearance rate (MCR) of insulin to be made at four separate steady state hormone concentrations spanning the physiological range. In normal subjects MCR was greatest at low insulin concentrations, falling from 24.7 ml/kg/min. at 16 μU/ml to 11.4 ml/kg/min. at a mean concentration of 280 μU/ml. In the OC group, MCR averaged 20.5 ml/kg/min. and did not change with increasing plasma insulin concentration. The plasma half-disappearance time (T 1/2) was longer than normal in the OC group (5·6 vs. 4·4 min., p < 0·05) despite a higher MCR. The prolonged T 1/2 indicated that the apparent distribution space was increased in those on OC (166·6 vs. 82·7 ml/kg., p < 0·0025). The results are interpreted as indicating increased capillary permeability to insulin and increased peripheral degradation. The fact that MCR did not fall in the OC group with increasing plasma insulin concentrations whereas it did in normal subjects, suggested that OC leads to the loss of saturable component of insulin degradation that is present in normal subjects. Insulin sensitivity (as judged by induced hypoglycaemia) was reduced in the OC group while growth hormone responses were within the normal range. Plasma cortisol was increased in those taking OC but the response to insulin induced hyperglycaemia was less marked than normal. The results indicate a significant alteration in insulin metabolism in these subjects, which may contribute to the impairment of carbohydrate tolerance seen in some women taking combined OC.     

Insulin Metabolism, Insulin Sensitivity and Hormonal Responses to Insulin Infusion in Patients Taking Oral Contraceptive Steroids

Abstract. The metabolism of unlabelled human monocomponent insulin was studied in a group of six patients being treated with combined oestrogen-progestogen oral contraceptives (OC) and conroared with a group of ten normal subjects. The parameters of insulin metabolism ware determined by a priming dose - continuous infusion technique which enabled measurements of metabolic clearance rate (MCR) of insulin to be made at four separate steady state hormone concentrations spanning the physiological range. In normal subjects MCR was greatest at low insulin concentrations, falling from 24. 7 ml/kg/min. at 16 μU/ml to 11. 4 ml/kg/min. at a mean concentration of 280 μU/ml. In the OC group, MCR averaged 20.5 ml/kg/min. and did not change with increasing plasma insulin concentration. The plasma half-disappearance time (T 1/2) was longer than normal in the OC group (5. 6 vs. 4. 4 min., p < 0. 05) despite a higher MCR. The prolonged T 1/2 indicated that the apparent distribution space was increased in those on OC (166. 6 vs. 82. 7 ml/kg., p < 0. 0025). The results are interpreted as indicating increased capillary permeability to insulin and increased peripheral degradation. The fact that MCR did not fall in the OC group with increasing plasma insulin concentrations whereas it did in normal subjects, suggested that OC leads to the loss of saturable component of insulin degradation that is present in normal subjects. Insulin sensitivity (as judged by induced hypoglycaemia) was reduced in the OC group while growth hormone responses were within the normal range. Plasma Cortisol was increased in those taking OC but the response to insulin induced hyperglycaemia was less marked than normal. The results indicate a significant alteration in insulin metabolism in these subjects, which may contribute to the impairment of carbohydrate tolerance seen in some women taking combined OC.     

Influence of fasting on adrenocortical and pancreatic islet response to glucose loads in the obese

Abstract The present study was undertaken in an attempt at unravelling the mechanisms involved in alteration of water and electrolyte balance occurring in the obese during fasting and refeeding. After a short control period, 8 obese patients were submitted to total fasting for 7 days, after which they received 200 g glucose orally in 1 dose each morning for 3 consecutive days. The intake of sodium and potassium was kept constant throughout. Body weight reduction during fasting was far in excess of what could be ascribed to negative caloric balance, on account of fluid and sodium chloride losses. Conversely, carbohydrate refeeding was associated with sodium chloride and water retention. Urinary sodium excretion exceeded intake during fasting despite the fact that aldosterone secretion rate (ASR) almost doubled, rising from 160 to 280 μg/24 h. After aldosterone was administered i.v. over 3 hours on the penultimate day of fasting, sodium excretion dropped from 62 to 22 mEq/24 h. Cortisol levels in plasma and urine remained normal during fasting. Unlike what was seen before the fast, glucose administration after 7 days without food resulted in a prompt decrease in sodium (from 34 to 6 mEq/24 h) and potassium (from 48 to 17 mEq/24 h) excretion; ASR and Cortisol values did not change appreciably at that time. Bicarbonate administered in order to correct the acidosis resulting from starvation, failed to reverse the negative sodium balance. After the fast, a marked deterioration of glucose tolerance was observed, despite an excessive insulin response, since plasma immunoreactive insulin levels at 3 hours were 2.5 times higher than those obtained during the control period. The hypothesis is raised that the accompanying sodium retention might be, at least in part, due to this increased insulin secretion.     

Insulin deficiency and insulin resistance in Type 2 (non-insulin-dependent) diabetes: quantitative contributions of pancreatic and peripheral responses to glucose homeostasis

A non-steady state dose-response study was designed to quantitate peripheral sensitivity to insulin and pancreatic responsiveness to glucose, and to assess their relative contribution to glucose intolerance in Type 2 diabetes (Type 2 DM, non-insulin-dependent). Eleven lean and eleven obese patients with mild diabetes (fasting plasma glucose, FPG, 10.3 +/- 1.0 and 9.4 +/- 0.6 mmol l-1, respectively) were examined; twenty-six lean and twelve weight-matched obese subjects served as controls. Pancreatic response was measured by sequential injection of 0.1, 0.3 and 0.9 g kg-1 glucose; peripheral sensitivity to insulin was determined from the rate of clearance (Kgluc) of 0.3 g glucose injected sequentially together with 25, 50 and 100 mU insulin kg-1 or with 0, 12.5 and 50 mU kg-1, under somatostatin infusion. The mean dose-response curve describing glucose-induced insulin release showed increased maximal capacity to secrete insulin in obese controls, while the responses of lean as well as obese Type 2 DM were reduced by more than 80%. The mean dose-response curves relating plasma exogenous insulin levels to Kgluc were similar in lean diabetics and lean controls. The curves of both obese controls and obese diabetics were shifted to the right, demonstrating similar insulin resistance. In four lean controls, sensitivity to insulin was tested also during a hyperglycemic clamp set at 10.3 +/- 0.6 mmol l-1. Hyperglycemia reduced the Kgluc at all insulin levels. Individual dose-response curves were transformed to single weighted numerical pancreatic responsiveness scores [PRS], and peripheral sensitivity scores [PSS].(ABSTRACT TRUNCATED AT 250 WORDS)     

In Vitro Studies of the Rate of Proinsulin and Insulin Turnover in Seven Human Insulinomas

Summary. Human insulinoma tissue excised from seven patients was incubated with glucose (3.0 mg/ml) and ³H-leucine (100 μCi/ml) for a 15 min. pulse period. One third of the tissue was homogenized immediately in 0.3 M sucrose (pH 6.0), one third was homogenized after a 20 min. chase (with L-leueine 37S μg/ml) and the remaining third after an 80 min. chase. Subcellular fractions (cell debris, mitochondria, secretory granules, microsomes and S-100) were prepared by centrifugation. Their identity was confirmed by ultrastructural examination. Since only tumours revealing typical β-granules were investigated the secretory granule fractions contained the same types of granules as found in the normal human B-cell.—The S-100 contained approximately 40% of the immuno-reactive insulin (IRI). The secretory granule samples from five tumours were fractionated by sucrose gradient ultracentrifugation. At the three time intervals examined, a peak of radioactivity and IRI was located at 1.60 M sucrose in three of the tumours. The different granule types were not separable in the sucrose gradients. Endogenous proinsulin-like components (proinsulin) and insulin were released throughout the incubation. During incubation of tumour tissue the ratio of IRI release to content was significantly higher than that from isolated human pancreatic islets. Newly synthesized proinsulin was detected in the medium after the 15 min. pulse in five of the tumours; radioactive proinsulin and insulin were present in all the media after the 20 and 80 min. chase periods. Islets isolated from the pancreatic tissue of two insulinoma patients showed a much slower proinsulin and insulin turnover.—These data support the conjecture that human insulinomas have a more rapid turnover of proinsulin and insulin than normal pancreatic islet tissue, apparently as the consequence of defective IRI storage and release mechanisms.     

Beta-cell function and insulin sensitivity contribute to the shape of plasma glucose curve during an oral glucose tolerance test in non-diabetic individuals

To clarify whether beta-cell function and/or insulin resistance contributes to the shape of plasma glucose curve during an oral glucose tolerance test (OGTT), we investigated 583 Japanese subjects with normal glucose tolerance (NGT, n = 306) or impaired glucose tolerance (IGT, n = 277). Each subject was subdivided into three shapes of plasma glucose curve as follows: monophasic pattern (M type), biphasic pattern (B type) and two peaks (T type). Homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index and insulinogenic index were assessed by plasma glucose and insulin concentrations obtained at fasting or during an OGTT. There was a greater proportion of M type in the IGT group (M = 80.9%, B = 15.5% and T = 3.6%), whereas the prevalence of B and T types was much higher in the NGT group (M = 66.6%, B = 26.5% and T = 6.9%). There were significant differences in the proportions of shape types between the NGT and IGT groups (p = 0.0006). Among the NGT category, insulin sensitivity was significantly higher in the B type than in the M type, and beta-cell function adjusted for insulin resistance was significantly higher in the B and T types than in the M type. Among the IGT category, no significant differences were seen among the three shape types with respect to insulin sensitivity, but the beta-cell function adjusted for insulin resistance was significantly lower in the M type than in the B and T types. In conclusion, both impaired insulin secretion and insulin resistance may contribute to the underlying mechanisms of the shape of plasma glucose curve in Japanese subjects.     

Association of visceral and subcutaneous fat with glucose intolerance, insulin resistance, adipocytokines and inflammatory markers in Asian Indians (CURES-113)

Objectives:

The aim of the study was to assess the association between visceral and subcutaneous fat with glucose intolerance, adipocytokines, inflammatory markers and carotid IMT in Asian Indians.

Design and methods:

Subjects with NGT (n = 85), IGT (n = 49) and T2DM (n = 93) were randomly selected from CURES. Total abdominal, visceral and subcutaneous fat were measured using Helical CT scan. Adiponectin, hs-CRP, TNF-alpha, oxidized LDL, visfatin and leptin and IMT and insulin resistance were assessed.

Results:

Total abdominal fat (p = 0.041) and the visceral fat (p = 0.039) but not subcutaneous fat progressively increased from NGT, IGT and T2DM subjects. With increasing quartiles of visceral fat, there was a significant increase in insulin resistance (p = 0.040); significant decrease in adiponectin (p = 0.043) and increase in TNF-alpha (p = 0.028), hs-CRP (p = 0.043), OX-LDL (p = 0.034) and visfatin (p = 0.040), and carotid IMT (p = 0.047) was observed.

Conclusion:

Visceral fat levels increased with increasing glucose intolerance and are associated with decreased levels of adiponectin and increased levels of hs-CRP, TNF-alpha, oxidized LDL, visfatin, HOMA-IR and IMT.