The role of glucagon in the pathogenesis of the endogenous hyperglycemia of diabetes mellitus.

The effect of glucagon suppression by somatostatin upon endogenous hyperglycemia was studied in three forms of experimental insulin deficiency in dogs: alloxan diabetes, total pancreatectomy, and diazoxide administration. In six insulin-requiring alloxan-diabetic dogs deprived of insulin for 24 hr, mean plasma glucose declined to 77% +/- 6% of the baseline level of 350 +/- 41 mg/dl during 3 hr of glucagon suppression, significantly below the unsuppressed saline controls (p less than 0.01-0.05). When somatostatin was discontinued, glucagon rose and glucose increased 21% (p less than 0.05) in 30 min. Significant correlation between maximal changes in glucagon and glucose was observed (r = 0.81; p less than 0.001). Even during a 1-hr alanine infusion in such dogs, glucose declined an average of 36 +/- 9 mg/dl, instead of rising 51 +/- 7 mg/dl as in unsuppressed controls. Maximal changes in glucagon and glucose were correlated (r = 0.85; p less than 0.01). In eight depancreatized dogs pretreated intravenously with continuous insulin and glucose infusions, withdrawal of insulin was followed by a rise in extrapancreatic glucagon; mean plasma glucose rose from 212 +/- 43 to 415 +/- 80 mg/dl 270 min after the end of the insulin infusion. However, when glucagon was suppressed after insulin withdrawal, glucose remained below 240 mg/dl, significantly less than the controls (p less than 0.005); when somatostatin was stopped, glucagon rose and glucose increased 88 +/- 19 mg/dl within an hour. The rises in glucagon and glucose were significantly correlated (r = 0.68; p less than 0.05). Glucagon suppression by somatostatin during diazoxide-induced blockade of insulin secretion in four normal dogs reduced hyperglycemia significantly but did not prevent it. The results support the hypothesis that a relative or absolute excess of glucagon, as well as a relative or absolute deficiency of insulin, is etiologically important in the development of endogenous hyperglycemia in diabetes mellitus, the hyperglucagonemia probably mediating the glucose overproduction.     

Metabolic effects of cortisol in man--studies with somatostatin

The metabolic effects of chronic hypercortisolaemia were studied by administration of tetracosactrin-depot, 1 mg I.M. daily for 36-60 hr to normal subjects. Partial insulin and glucagon deficiency were induced at the end of the period by infusion of somatostatin, 100 micrograms/h for 210 min. Tetracosactrin alone induced a three fold rise in basal serum cortisol levels and fasting blood glucose concentration rose from 5.2 +/- 0.2 to 7.2 +/- 0.2 mmole/l (p less than 0.01) with a rise in fasting serum insulin from 5.2 +/- 1.2 to 13.1 +/- 1.9 mU/l (p less than 0.02). Concentrations of the gluconeogenic precursors lactate, pyruvate and alanine were also raised, but non-esterified fatty acid, glycerol and ketone body levels were unchanged. Somatostatin infusion caused a 30%-50% decrease in serum insulin and a 20%-60% decrease in plasma glucagon concentrations both before and after tetracosactrin administration. A similar rise in blood glucose concentration, relative to the saline control, occurred over the period of somatostatin infusion both with and without elevated cortisol levels. However, prior tetracosactrin administration caused a 100% greater rise in blood ketone body concentrations during infusion of somatostatin than was seen in the euadrenal state, despite similar plasma NEFA concentrations. Hypercortisolaemia causes hyperglycaemia and elevated gluconeogenic precursor concentrations but the associated rise in serum insulin concentrations limits lipolysis and ketosis. In insulin deficiency, a ketotic effort of glucocorticoid excess is evident which may be independent of lipolysis and occurs despite concurrent glucagon deficiency. These catabolic actions of cortisol are likely to be of major importance in the metabolic response to stress.     

Effects of a thiazide diuretic (hydroflumethiazide) and a loop diuretic (bumetanide) on the endocrine pancreas: studies in vitro

Treatment with thiazide diuretics causes an impairment of the glucose metabolism. To study whether this is due to a direct effect on the endocrine pancreas, the effects of the thiazide hydroflumethiazide on the release of glucagon, insulin, and somatostatin from the isolated perfused pancreas of normal and alloxan diabetic dogs were examined. Hydroflumethiazide at concentrations ranging from 1 to 50 micrograms/mL stimulated the normal secretion of glucagon (P less than 0.001), insulin (P less than 0.001), and somatostatin (P less than 0.001) in a dose-dependent manner. The normal hormone responses evoked by 50 micrograms/mL of the thiazide were, however, modified by the prevailing glucose level: higher insulin (P less than 0.05) and somatostatin (P less than 0.05) and lower glucagon (P less than 0.05) were obtained at the high glucose concentration of 11 mmol/L rather than at the low glucose concentration of 1.3 mmol/L. In alloxan diabetes, insulin secretion was almost extinct and did not respond to hydroflumethiazide, whereas glucagon was dose-dependently stimulated (P less than 0.001). In addition, we looked at the effect of the loop diuretic, bumetanide. The infusion of bumetanide at doses ranging from 0.5 to 3 micrograms/mL did not alter the release of glucagon, insulin, and somatostatin in the presence of 5.5 mmol/L glucose. The results suggest that hydroflumethiazide possesses the ability to directly stimulate A cell secretion in the normal and alloxan diabetic pancreas. Whether this effect is of clinical importance for the diminution in glucose tolerance observed during thiazide therapy remains, however, uncertain.     

The physiologic action of insulin on glucose uptake and its relevance to the interpretation of the metabolic clearance rate of glucose

Glucose uptake (Ru) is dependent upon the concentrations of both glucose and insulin. The metabolic clearance rate of glucose (MCRG), has been used as an in vivo measure of insulin action, because it was said to be independent of the prevailing glucose concentration. The validity of this assumption has recently been challenged. In this study, the effect of insulin concentration on the rate of glucose uptake (Ru) and on the MCRG was studied during euglycemia (5.1 +/- 0.3 mmol/L) and moderate hyperglycemia (10.4 +/- 0.5 mmol/L) in 17 experiments on nine normal ambulant volunteers. Stable plasma insulin levels were maintained with fixed infusion rates of insulin (0-300 mU/kg/h) and somatostatin (7.5 micrograms/min). At low insulin concentrations (less than 5 microU/mL) the increase in glucose uptake in response to hyperglycemia was small (5.3 +/- 2.3 mumol/kg/min). In contrast, with insulin levels more than 25 microU/mL, there was a steep rise in glucose uptake with hyperglycemia (55 +/- 3 mumol/kg/min; range: 44-74 mumol/kg/min). The metabolic clearance rate of glucose fell by an average of 32% with hyperglycemia in the studies at the lowest insulin levels (2.2 +/- 0.6 v 1.5 +/- 0.1 mL/kg/min; 0.15 greater than P greater than 0.1). There was no change in the MCRG in the subjects studied at higher insulin levels. It is concluded that (1) low concentrations of insulin are essential for the increase in glucose disposal during hyperglycemia; and (2) provided insulin levels are more than 25 microU/mL and plasma glucose less than 11 mmol/L, MCRG is independent of the plasma glucose concentration and is therefore a valid measure of insulin-mediated glucose uptake.     

Effect of the somatostatin analog D-Trp8,D-Cys14 on glucose insulin, pancreatic glucagon and growth hormone plasma levels in acromegalics and mild diabetics

The effect of the somatostatin analog (GHRIH-A) D-Trp8, D-Cys14 on plasma levels of growth hormone, pancreatic glucagon, insulin and glucose was studied in four acromegalic patients and in four maturity-onset mild diabetics. Acromegalics received a bolus iv injection of 25 microgram of GHRIH-A, followed by a continuous infusion of 25 microgram in saline over an hour. Mild diabetics were submitted in two different days to two tests: arginine (30 g in 30 min) +/- GHRIH-A (bolus iv injection of 25 microgram followed by an infusion of 25 microgram/h over 120 min) and arginine + saline. GHRIH-A lead to a significant (2 p less than 0.01) fall in GH basal secretion in acromegalics, and significantly reduced the GH response to arginine in maturity-onset diabetics. The inhibitory effect of insulin secretion was less impressive, but significative in both groups. No significant changes in plasma pancreatic glucagon values were noted. In mild diabetics, GHRIH-A infusion induced a small but significant increase in the blood glucose increment due to arginine. Our data suggest that this somatostatin analog may be potentially useful only when GH suppression is the main therapeutic goal to be reached, as in acromegaly and in severe diabetic retinopathy, but not in metabolic control of mild diabetic patients with a good residual insulin secretion.     

Nature and biologic activity of “extrapancreatic glucagon”: Studies in pancreatectomized cats

After total pancreatectomy concentrations of circulating immunoreactive glucagon (IRG) were elevated (255 ± 37 pg/ml, mean ± SEM; n = 20) in comparison to unoperated cats (119 ± 27 pg/ml). Plasma glucagon concentrations were determined in an assay regarded as specific for pancreatic glucagon. The nature of this extrapancreatic IRG was further examined in the following studies. Arginine (0.45 gm/kg i.v.) caused a marked elevation of IRG in normal animals but did not cause a consistent elevation of IRG in 6 pancreatectomized cats. Whereas somatostatin (20 μg/kg/hr i.v. for 1 hr) in 10 pancreatectomized cats caused a reduction in IRG from 195 ± 45 to 64 ± 22 pg/ml (p < 0.02), blood glucose did not change. Moreover, insulin (0.22 U/kg/hr i.v. for 1 hr) failed to reduce blood glucose levels in 6 pancreatectomized cats despite a fall in IRG from 269 ± 87 to 150 ± 62 pg/ml (p < 0.05). Glucagon (4 ng/kg/min i.v. for 1 hr) given during the second hour of somatostatin infusion failed to raise blood glucose in 7 untreated pancreatectomized cats. However, when euglycemia was achieved by prolonged insulin therapy in 2 pancreatectomized animals, extrapancreatic IRG became completely suppressed and a hyperglycemic response to exogenous glucagon was restored. Although extrapancreatic IRG appeared identical to pancreatic glucagon by immunoassay, Sephadex G50 chromatography of plasma from 4 pancreatectomized animals showed that 40%–90% of the IRG was of approximately 9000–10,000 molecular weight. Only 10%–60% was of molecular weight corresponding to pancreatic glucagon, i.e., 3500. This contrasted with normal cats, in whom more than 90% of IRG was of molecular weight 3500. The excessive secretion of extrapancreatic IRG is probably related to insulin deficiency since it is reversed by prolonged insulin therapy. The circulating material is heterogeneous and would correspond in molecular size to pancreatic glucagon and a larger molecular weight glucagon precursor. The lack of a consistent response to arginine and predominance of 9000–10,000 molecular weight material could be due to chronic hyperstimulation of true A cells situated in the upper gastrointestinal tract or other extrapancreatic sites; on the other hand, these results could suggest that the cell of origin of extrapancreatic IRG is distinct from the A cell. A major role for extrapancreatic glucagon in the hyperglycemia of diabetes is not evident in these studies, though hepatic glycogen depletion and a reduced rate of peripheral glucose utilization in the operated animals may have reduced the impact on blood glucose levels of changes in IRG. It is possible that extrapancreatic IRG contributes to the poor response to exogenous insulin and glucagon seen in untreated pancreatectomized animals.     

A COMPARISON OF THE EFFECT OF LEVODOPA AND SOMATOSTATIN ON THE PLASMA LEVELS OF GROWTH HORMONE, INSULIN, GLUCAGON AND PROLACTIN IN ACROMEGALY

The acute suppressive effects of L-dopa and somatostatin (growth hormone release inhibiting hormone) on the elevated plasma GH concentrations of seven patients with acromegaly were compared. In addition the effects of the two agents on fasting concentrations of plasma glucose, insulin, glucagon and prolactin were studied. In six of the seven patients hourly samples for GH assay were taken from 08.00 to 20.00 hours on a control day. Synthetic cyclic somatostatin (100 mug) was infused intravenously in an albumin/saline solution over 75 min with a Harvard constant infusion pump. Levodopa 500 mg was given orally. Somatostatin infusion produced a reduction in plasma GH concentrations in six of seven patients (mean reduction 55%). L-Dopa produced a reduction in plasma GH concentrations in the same six patients (mean reduction 52%). The minimum GH concentrations achieved in the two tests were comparable and did not differ significantly from the minimum GH concentrations recorded during the 12 h control study. Mean plasma insulin and glucagon concentrations were also significantly reduced during the somatostatin infusion (P less than 0-025; P less than 0-05 respectively). Plasma glucose concentrations did not change. L-Dopa did not alter mean plasma glucose, insulin or glucagon values. Somatostatin did not alter prolactin values but L-Dopa suppressed basal values to less than 2 ng/ml in five patients. This study shows that the plasma GH change after the administration of L-dopa and somatostatin in acromegaly is comparable and confirms the pancreatic effects of somatostatin.     

Effect of phentolamine on the somatostatin-induced inhibition of glucagon and insulin secretion.

Synthetic cyclic somatostatin was infused into either the cranial pancreaticoduodenal artery or the femoral vein of anesthetized dogs with or without previous administration of phentolamine. Somatostatin infused into the pancreatic artery at a dose of 50 ng/kg/min for 10 min caused significant decreases in blood flow and plasma basal concentrations of both glucagon and insulin in the cranial pancreaticoduodenal vein, resulting in a profound decline of bihormonal output during the infusion. Arterial plasma glucose was not reduced during the administration of somatostatin in the pancreatic artery. These somatostatin-induced decreases failed to be eliminated by a 0.2 mg/kg injection of phentolamine into the femoral vein followed by a 9-min infusion of this alpha-adrenergic blocker (0.02 mg/kg/min) into the pancreatic artery immediately prior to the somatostatin administration. An inhibition of glucagon and insulin output and a fall of plasma glucose caused by somatostatin (1.7 microgram/min) infused into the femoral vein for 30 min also were not abolished by a prolonged and simultaneous infusion of phentolamine (0.2 mg/min) into the femoral vein over a period of 2 hr. These results indicate that alpha-adrenergic receptor mechanisms do not play a major role in the inhibition of islet glucagon and insulin secretion by somatostatin.     

Insulin insensitivity in offspring of parents with type 2 diabetes mellitus

Measurements were made of the plasma glucose and insulin responses to a 75 g oral glucose challenge in 50 Chinese born in Taiwan, divided into two groups on the basis of family history of Type 2 diabetes. Twenty-five individuals (age 29 +/- 5 (+/- SD) years) had 2 parents with normal oral glucose tolerance, whereas at least 1 parent had Type 2 diabetes in the other 25 subjects (age 30 +/- 6 years). In addition, in vivo insulin action was estimated by determining the steady-state plasma glucose concentration during a 3-h continuous infusion of glucose, insulin, and somatostatin. Steady-state plasma glucose concentration was used as a measure of insulin-induced glucose disposal. The 50 subjects were non-obese, and of comparable gender distribution and body mass index. Plasma glucose and insulin concentrations in response to oral glucose were similar in the two groups. However, the steady-state plasma glucose concentration was significantly (p less than 0.01) higher in offspring with a family history of Type 2 diabetes when compared by two-way analysis of variance (mean +/- SE was 5.87 +/- 0.27 vs 5.12 +/- 0.32 mmol l-1). This difference was found despite a significantly (p less than 0.01) higher steady-state plasma insulin concentration during the infusion studies (0.705 +/- 0.027 vs 0.643 +/- 0.025 nmol l-1) in offspring of people with diabetes. The results support the view that resistance to insulin-stimulated glucose uptake is present in offspring of diabetic parents.     

Metabolic interactions of glucagon and cortisol in man--studies with somatostatin

The metabolic response to pathophysiologic concentrations of glucagon, induced by glucagon infusion, has been examined in normal man before and after 36-60 hr hypercortisolaemia, induced by administration of tetracosactrin-depot. Glucagon alone increased serum insulin levels twofold but blood glucose was unaltered. Plasma NEFA and blood ketone body concentrations were decreased by glucagon infusion. Tetracosactrin produced a threefold rise in serum cortisol levels and caused mild fasting hyperglycemia and hyperinsulinaemia. Subsequent glucagon infusion had no effect on circulating insulin, glucose, NEFA or ketone body concentrations. Simultaneous infusion of somatostatin, to produce partial insulin-deficiency, unmasked a hyperglycemic action of glucagon (+ 3.8 +/- 0.2 mmol/l at 90 min, p less than 0.02). This glucagon-induced rise in blood glucose was diminished by prior tetracosactrin administration. Tetracosactrin revealed a mild lipolytic action of glucagon in partial insulin deficiency, not apparent in the euadrenal state. Glucagon was equally hyperketonemic during somatostatin infusion before and after tetracosactrin. Thus the hyperglycemic and hyperketonemic actions of glucagon at pathophysiologic levels are restricted to insulin deficiency. Hypercortisolaemia reveals a lipolytic action of glucagon in insulin-deficient man but does not potentiate the hyperglycemic or hyperketonemic effects.     

Glucose homeostasis during prolonged suppression of glucagon and insulin secretion by somatostatin.

Somatostatin was infused for 5-8 hr into five normal men and eleven normal, conscious dogs. This infusion resulted in a persistent decline in plasma glucagon (40-60%) and insulin (30-45%). Plasma gluccose fell 15-25% during the initial 1-2 hr, but subsequently rose to hyperglycemic levels (130-155 mg/100ml) by 3-6 hr, despite persistent hypoglucagonemia. Glucose production initially declined by 40-50%, but later rose to levels 15-20% above basal rates while peripheral glucose utilization fell to levels 20-30% below basal, thereby accounting for hyperglycemia. Infusion of exogenous insulin so as to restore plasma insulin to preinfusion values or cessation of the somatostatin infusion with restoration of endogenous insulin secretion resulted in a prompt reduction of plasma glucose to baseline values. Prevention of the initial somatostatin-induced hypoglycemic response by intravenous infusion of glucose failed to prevent the delayed hyperglycemia. We conclude that somatostatin caused only transient hypoglycemia in normal subjects and that hyperglycemia eventually developes as a consequence of insulin deficiency. These data indicate that basal glucagon secretion is not essential for the development of fasting hyperglycemia and support the conclusion that insulin deficiency rather than glucagon excess is the primary factor responsible for abnormal glucose homeostasis in the diabetic.     

Effect of somatostatin and a glucagon-specific analog on glucose homeostasis during arginine infusion

The glucose response to arginine infusion in normal rats was studied during insulin and glucagon deficiency (somatostatin infusion, 1 mg/kg/hr) or selective glucagon deficiency ([D-Cys¹⁴]-somatostain infusion, 1 mg/kg/hr). In control studies, plasma glucose levels rose 14 mg/dl in response to arginine and returned to basal levels at the termination of the infusion. Insulin levels increased 136 ± 12 μU/ml and glucagon increased 76 ± 12 pg/ml during the infusion. Infusion of somatostatin resulted in supression of both arginine-induced insulin and arginine-induced glucagon release, and marked hyperglycemia ensued. The administration of [D-Cys¹⁴]-somatostatin during arginine infusion produced no associated hyperglycemia. It resulted in suppression of glucagon secretion and a modest rise in insulin release. These results demonstrate that the hyperglycemic effects of somatostatin in arginine-treated animals do not arise in animals treated with glucagon-specific somatostatin analogs.     

Effect of experimental potassium deficiency on glucose and insulin metabolism

Disturbances in glucose and insulin metabolism frequently accompany a variety of clinical states associated with potassium deficiency. The exact role of the potassium deficit and the mechanism of its effect are in doubt. The glucose-clamp technique was therefore employed to study glucose and insulin metabolism in 7 normal young male subjects before and after induction of potassium depletion. The clamp technique places the blood glucose concentration under the investigator's control. Under the conditions of steady state hyperglycemia (125 mg/dl above basal for 2 hr) it provides quantification of (1) pancreatic beta cell sensitivity to glucose (plasma insulin response), (2) glucose tolerance (glucose metabolized), and (3) tissue sensitivity to insulin (glucose metabolized/insulin response). Potassium deficiency was induced during a 7–8 day period of a weight-maintaining diet containing 40 meq potassium and at least 150 g carbohydrate, along with the administration of 60 g Na polystyrene sulfonate daily. Paired analysis showed a significant decline in the amount of glucose metabolized from pre- to postdepletion (?27.4 ± 4.5%, p < 0.01). This decline in carbohydrate tolerance was associated with a significant decrease in plasma insulin response to sustained hyperglycemia (?26% ± 6.9%, p < 0.02). Potassium depletion had no effect on tissue sensitivity to insulin (+1.7 ± 7.8%). The degree of potassium depletion as estimated by change in total body ⁴⁰K ranged from 1.0% to 8.4% and correlated with the decrease in insulin response (r = 0.78, p < 0.05). This study demonstrates that potassium depletion causes glucose intolerance, which is associated with impaired insulin secretion.     

Failure of fasting to influence the GIP response to oral glucose in non-obese human subjects

The plasma GIP response to an oral 50 g glucose tolerance test has been compared in eight non-obese human subjects after 12 and 36 h of fasting. Basal plasma GIP and basal plasma insulin concentrations were similar after 12 and 36 h of fasting. Basal blood glucose was lower after 36 h fasting than after 12 h fasting (p less than 0.0125). After 36 h fasting the oral glucose tolerance test stimulated higher blood glucose concentrations at 60, 90 and 120 min (p less than 0.0125) and higher plasma insulin concentrations at similar time points (p less than 0.05), but stimulated plasma GIP concentrations were similar after 12 and 36 h fasts. These findings show that the increased insulinotrophic effect of oral glucose after 36 h fasting in non-obese subjects is not due to an associated augmentation of the glucose-induced GIP response.     

The glucoregulatory response to intravenous glucose infusion in normal man: Roles of insulin and glucose

In order to differentiate the roles of hyperinsulinemia and hyperglycemia per se in the homeostatic response to i.v. glucose administration, two groups of normal subjects were given either glucose alone (3.5 mg kg^?1 min^?1) or glucose (3 mg kg^?1 min^?1) in conjunction with somatostatin (500 μg hr^?1), insulin (0.15 mU kg^?1 min^?1) and glucagon (1 ng kg^?1 min^?1). Glucose kinetics were measured by the primed-constant infusion of 3-³H-glucose. During the infusion of glucose alone, plasma glucose stabilized at levels 45–50 mg/dl above the fasting values. Endogenous glucose output was markedly suppressed by 85%–90% while glucose uptake rose to values very close to the infusion rate of exogenous glucose. Glucose clearance remained unchanged. Plasma insulin rose three-fourfold while plasma glucagon fell by 25%–30%. When glucose was infused with somatostatin, insulin, and glucagon, plasma insulin was maintained at levels 50% above baseline while glucagon remained at preinfusion levels. Under these conditions, the infusion of exogenous glucose resulted in a progressive increase of plasma glucose which did not stabilize until the end of the study period (190 mg/dl at 120 min). Endogenous glucose production was consistently suppressed (52%) but significantly less than observed with the infusion of glucose alone (p < 0.01). Glucose uptake increased to the same extent as with glucose alone, despite the more pronounced hyperglycemia. Thus, glucose clearance fell significantly below baseline (25%–30%; p < 0.01). These data demonstrate that hyperglycemia per se (fixed, near basal levels of insulin and glucagon) certainly contributes to the glucoregulatory response to i.v. glucose administration by both inhibiting endogenous glucose output and increasing tissue glucose uptake. However, the extra-insulin evoked by hyperglycemia is necessary for the glucoregulatory system to respond to the glucose load with maximal effectiveness.     

Can insulin resistance exist as a primary defect in noninsulin-dependent diabetes mellitus?

In this study we have attempted to quantify the plasma insulin response to glucose and insulin action in 22 nonobese subjects: 11 with normal glucose tolerance and 11 with mild [mean fasting plasma glucose concentration, 128 +/- (+/- SEM) 5 mg/dL] noninsulin-dependent diabetes mellitus (NIDDM). Estimates of the plasma insulin response were made by determining the plasma insulin concentration at hourly intervals from 0800-1600 h, before and after mixed meals consumed at 0800 h (breakfast) and 1200 h (lunch). Insulin action was assessed by measuring glucose uptake during insulin clamp studies performed at steady state plasma insulin levels of approximately 10 and 60 microU/mL, with the difference between the 2 values defined as insulin-stimulated glucose uptake. Plasma glucose (P less than 0.001) and insulin (P less than 0.001) concentrations were significantly higher in patients with NIDDM throughout the 8-h period (by two-way analysis of variance). However, mean (+/- SEM) insulin-stimulated glucose uptake was markedly reduced (P less than 0.001) in patients with type 2 diabetes mellitus (112 +/- 72 vs. 336 +/- 44 mg/m2 min-1). Thus, patients with NIDDM and mild fasting hyperglycemia were both insulin resistant and hyperinsulinemic compared to normal individuals. These data indicate that a defect in insulin-stimulated glucose uptake can occur in NIDDM in the absence of significant hyperglycemia and/or hypoinsulinemia.     

Hypolipidemic effects of metformin in hyperprebetalipoproteinemia.

Metformin's hypolipidemic effects (2.55 g/day for 3 months) have been studied in 19 subjects with Fredrickson's Type IV hyperprebetalipoproteinemia. The majority of patients were above ideal body weight (relative body weight = 118 +/- 2.7 %). Eleven of the subjects presented chemical diabetes, 5 fasting hyperglycemia, and 3 normal glucose tolerance. After treatment with metformin, body weight showed a slight, but significant reduction (--2.4 +/- 0.3 kg). Glucose tolerence was not substantially altered while basal glucose was significantly reduced in the 5 subjects with fasting hyperglycemia. Basal plasma insulin was significantly reduced in all the patients following metformin treatment. Insulin response to OGTT was slightly reduced in the subjects with fasting hyperglycemia. Independent of the patients' glucose tolerance, metformin treatment induced a marked decrease in plasma triglycerides (-- 40 %) and a reduction in plasma cholesterol (-- 12 %). No correlation was found between triglyceride and cholesterol reduction and body weight, glucose, and plasma insulin variations. Like phenformin, metformin acts not only on glucose metabolism and insulin secretion but on lipid metabolism as well.     

Pancreatic hormones in streptozotocin-diabetic rats

Summary Pancreatic polypeptide (PP) levels of plasma and pancreas were studied in the rat after streptozotocin (STZ) injection. In 4 weeks of observation, plasma PP was elevated up to 4 times the control values with marked hyperglycemia and insulinopenia. At 4 weeks, intravenous (i.v.) glucose tolerance tests and i.v. insulin tolerance tests were performed. In the glucose tolerance test, control rats responded with a 10-fold increase in plasma insulin and 15% decrease in plasma PP levels, whereas STZ-diabetic rats produced no increase of plasma insulin and an approximately 50% reduction of plasma PP levels with marked hyperglycemia. In the insulin tolerance test, diabetic rats showed a marked increase in plasma PP levels and less increase in plasma insulin levels than the controls. In diabetic rats, pancreatic insulin levels were reduced to about 3.5% of control, whereas those of somatostatin (SRIF), PP and glucagon were elevated to 8.3, 2.7 and 1.4 times control, respectively. In a morphometric study, islet areas of diabetic rats were seen to be reduced to about 10% of control. With in vitro perfused pancreatic slices, STZ-diabetic pancreas released much more glucagon and PP than control pancreas. Thus, STZ injection in the rat caused marked β-cell damage as well as hyperplasia of SRIF, PP and glucagon cells, with glucagon and PP hypersecretion.     

Pancreatic hormones in streptozotocin-diabetic rats

Pancreatic polypeptide (PP) levels of plasma and pancreas were studied in the rat after streptozotocin (STZ) injection. In 4 weeks of observation, plasma PP was elevated up to 4 times the control values with marked hyperglycemia and insulinopenia. At 4 weeks, intravenous (i.v.) glucose tolerance tests and i.v. insulin tolerance tests were performed. In the glucose tolerance test, control rats responded with a 10-fold increase in plasma insulin and 15% decrease in plasma PP levels, whereas STZ-diabetic rats produced no increase of plasma insulin and an approximately 50% reduction of plasma PP levels with marked hyperglycemia. In the insulin tolerance test, diabetic rats showed a marked increase in plasma PP levels and less increase in plasma insulin levels than the controls. In diabetic rats, pancreatic insulin levels were reduced to about 3.5% of control, whereas those of somatostatin (SRIF), PP and glucagon were elevated to 8.3, 2.7 and 1.4 times control, respectively. In a morphometric study, islet areas of diabetic rats were seen to be reduced to about 10% of control. With in vitro perfused pancreatic slices, STZ-diabetic pancreas released much more glucagon and PP than control pancreas. Thus, STZ injection in the rat caused marked beta-cell damage as well as hyperplasia of SRIF, PP and glucagon cells, with glucagon and PP hypersecretion.     

Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin

We previously demonstrated that supraphysiological insulin concentrations reduced the plasma 34K insulin-like growth factor-binding protein (IGF-BP) concentrations in humans. In this study we examined whether physiological changes in plasma insulin concentrations regulate IGF-BP and, if so, whether the regulation is influenced by race, glucose tolerance, or rate of glucose metabolism. For these purposes we 1) analyzed the relationship between fasting plasma insulin and IGF-BP concentrations in 2 racial groups (23 caucasians and 35 southwestern American Indians), 2) measured the response of plasma IGF-BP to oral glucose in 20 normal subjects, and 3) determined the dose-response characteristics of plasma IGF-BP to glucose and insulin in 23 normal subjects at 4 different insulin and glucose concentrations. The fasting plasma insulin concentration was inversely related to the plasma IGF-BP concentration in both the caucasian and Indian groups (P less than 0.0001). In the caucasian group the mean plasma IGF-BP concentration was higher [15 +/- 4 (+/- SE) micrograms/L] than in the Indian group (8 +/- 2 micrograms/L; P less than 0.05). This difference was independent of race and glucose tolerance, and it could be explained by lower plasma insulin concentrations in the caucasian (387 +/- 50 pmol/L) than in the Indian group (215 +/- 43 pmol/L; P less than 0.001). After oral glucose administration, the insulin concentration (423 +/- 72 pmol/L) was maximal 30 min after glucose treatment, and significant suppression of the IGF-BP concentration occurred at 90 min. Analysis of the dose-response curves revealed maximal suppression of IGF-BP at about 1150 pmol/L insulin, and half-maximal suppression at about 290 pmol/L. The plasma glucose concentration or the rate of glucose metabolism had no effect on the IGF-BP concentration. These data suggest that insulin is a major regulator of plasma IGF-BP concentrations under physiological conditions.