Citations

Glucose clearance (glucose utilization ÷ plasma glucose) is commonly used to assess glucose utilization under conditions in which plasma glucose concentrations vary. The validity of this practice requires that glucose clearance itself be independent of plasma glucose concentration. The present studies were, therefore, undertaken to determine the relationship between glucose clearance and plasma glucose concentration in man. Using the glucose clamp technique, rates of glucose utilization (measured isotopically with 3-3H-glucose) and glucose clearance were determined in 5 normal volunteers at steady-state plasma glucose concentrations of approximately 60, 95,130, and 165 mg/dl, while plasma insulin concentrations were maintained constant (∼18 μU/ml) by infusion of insulin and somatostatin. Despite virtually identical 0.4 mg · kg−1 · min−1 increments in glucose utilization for each 35-mg/dl increment in plasma glucose, glucose clearance decreased as a function of plasma glucose concentration (r = − 0.85, P < 0.001). These results indicate that glucose clearance is not independent of changes in plasma glucose concentration and, thus, use of glucose clearance to evaluate glucose utilization at differing plasma glucose concentration is not valid. Whether this conclusion also applies to similar use of clearance for other substrates remains to be determined.

To determine the mechanism by which hyperinsulinemia causes hypoglycemia in insulinoma patients, rates of glucose production and utilization, and circulating levels of insulin, glucagon, alanine, lactate, and glycerol were measured in 6 insulinoma patients during development of fasting hypoglycemia and in 8 normal volunteers studied over an identical interval. Initially, insulinoma patients had a greater plasma insulin (42 ± 9 versus 15 ± 1 μU/ml) and glucagon levels (214 ± 31 versus 158 ± 21 pg/ml) than normal subjects, P < 0.05, but their plasma glucose levels (81 ± 4 mg/dl) and rates of glucose production and utilization (1.71 ± 0.08 and 1.74 ± 0.08 mg/kg min, respectively) were not significantly different from those of normal subjects (93 ± 2 mg/dl, 1.93 / 0.11, and 1.92 ± 0.13 mg/kg · min, respectively). During a subsequent 8-h fast, glucose production and glucose utilization decreased in both groups, but more markedly in insulinoma patients. Since glucose utilization exceeded glucose production to a greater extent in insulinoma patients than in normal subjects, plasma glucose decreased to 44 ± 3 mg/dl in insulinoma patients, but only to 84 ± 1 mg/dl in normal subjects (P < 0.001). Glucose utilization in insulinoma patients never exceeded that of normal subjects. These results demonstrate that fasting hypoglycemia in the insulinoma patients is usually due to suppression of glucose production rather than to acceleration of glucose utilization, as is widely thought. A direct effect of insulin on the liver is probably responsible, since circulating levels of gluconeogenic precursors are normal and since plasma glucagon increases during development of hypoglycemia in insulinoma patients.

A new bioartificial pancreas, in which rat islets within a Millipore chamber are perifused with blood ultrafiltrate (polyacrylonitrile membrane), has been developed and its function evaluated in vitro and in vivo. Use of ultrafiltration (instead of diffusion) permitted rapid transmission of changes in blood glucose to the islet compartment (less than 10 min). To determine whether ultrafiltrate of Krebs-Ringer bicarbonate buffer (KRBB) and blood could support normal islet Bcell function, insulin secretion of freshly isolated islets in response to a 20-mM glucose challenge was examined during perifusion with KRBB and then with ultrafiltrate produced either from KRBB itself or from blood of normal and streptozotocin-induced diabetic rats. In the latter case, perifusate was reinfused to the animals, whose plasma glucose and insulin were then measured. Insulin responses to glucose were virtually identical when the same islets were perifused with KRBB and then with ultrafiltrate of KRBB (47 ± 12 versus 41 ± 9 ng/100 islets/24 min), or when islets were perifused with KRBB and then with ultrafiltrate produced from blood of normal rats (69 ± 6 versus 73 ± 11 ng/100 islets/24 min). When five diabetic rats were connected to the device containing 600 islets, their plasma glucose decreased from 19.8 ± 1.2 to 6.1 ± 0.5 mM (P < 0.001) within 120 min without overshoot hypoglycemia, and remained normal for up to 6 h. Plasma insulin increased from 2.0 ± 0.1 to 11.4 ± 1.4 ng/ml (P < 0.02) at 30 min and then decreased to 2.9 ± 0.6 ng/ml. After intravenous glucose administration (0.5 g/kg, N = 4), plasma insulin increased twofold within 15 min, and glucose disappearance rates were identical to those obtained in four normal rats (K = 2.13 ± 0.18 versus 2.23 ± 0.09, NS). These results indicate that ultrafiltrate of KRBB and blood can acutely support normal islet B-cell function, and that ultrafiltration can provide satisfactory glucose-insulin kinetics for an implantable closed-loop insulin delivery system, in which nonsyngeneic islets may be protected against immune rejection.

To determine whether receptor and/or postreceptor abnormalities of insulin action were responsible for insulin resistance in nonobese patients with non-insulindependent diabetes mellitus (NIDDM) and to assess the role of insulin resistance in their impaired glucose tolerance, insulin dose-response characteristics, insulin binding to monocytes, and insulin secretion were compared in 10 nonobese patients with NIDDM and six age-weight-matched nondiabetic volunteers. The insulin resistance of the diabetics was characterized by a shift to the right of their insulin dose-response curve (Km 81 ± 4 μU/ml vs. 58 ± 2 μU/ml in the nondiabetics P < 0.001) but a normal maximal response to insulin. Although monocyte insulin binding was decreased in the diabetics (P < 0.01), their response to insulin was appropriate for the number of insulin receptors occupied indicating normal postreceptor function. Insulin secretion was markedly reduced in diabetic subjects (52 ± 22 vs. 471 ± 90μu.U · ml−1 · 10 mirr1 in the nondiabetic subjects, P < 0.001) and was more strongly correlated with fasting plasma glucose (r = 0.92, P < 0.001) and intravenous glucose tolerance (Kivgtt) (r = 0.98, P < 0.001) than was insulin sensitivity (Km) (r = 0.23, NS, and r = 0.57, P < 0.05, respectively). We conclude that in nonobese patients with NIDDM, insulin resistance is characterized by a shift to the right of the insulin dose-response curve, which can be accounted for solely by an insulin receptor defect. However, in these patients, impaired insulin secretion rather than insulin resistance appears to be the predominant metabolic abnormality.

Rapid axonal transport was studied by several methods in rats with serum glucose levels above 300 mg/dl as a result of treatment with streptozotocin (45–50 mg/kg) 3 days, 1 wk, 4 wk, 8 wk, or 4 mo earlier. With untreated age-matched rats as controls, rapid anterograde axonal transport in the sciatic nerves of diabetic rats appeared entirely normal. Statistically significant differences were never observed between experimental and control nerves in the basal content of acetylcholinesterase (AChE) and dopamine-β-hydroxylase (DBH) activity or in the rate of accumulation of these enzymes proximal or distal to a ligature. Therefore, the basic capacity for rapid anterograde and retrograde axonal transport of proteins was probably unimpaired in the diabetic nerves. The accumulation of labeled glycoproteins proximal to ligatures on the contralateral nerves of the same rats after injection of the L5 dorsal root ganglion with 3H-fucose was likewise normal. However, rats with 1, 4, and 8 wk of diabetes did show reduced accumulation of fucose-labeled protein distal to nerve ligations, indicating a long-lasting abnormality of retrograde axonal transport. Furthermore, this abnormality was reversed by daily insulin treatment during the second half of an 8-wk experimental period. It is therefore unlikely that the depression of retrograde transport reflects direct toxic effects of streptozotocin. We conclude that streptozotocin-induced diabetes leads to: (1) abnormal delay in the turnaround of transported proteins in distal nerve regions, perhaps combined with (2) an abnormal metabolism of glycoproteins. A delayed onset of retrograde transport is consistent with present observations of reduced accumulation of 125I-labeled nerve growth factor (NGF) below a midthigh ligature on the sciatic nerve after injection of this protein into the hindfoot of rats with 3–5 wk of diabetes. Further work on the factors controlling rapid retrograde transport of proteins in diabetic nerve is warranted.

To assess the effects of endogenous somatostatin on pancreatic islet A- and B-cell function, isolated rat islets were incubated in antisomatostatin γ-globulin to bind endogenously released somatostatin, and the insulin and glucagon secretion of these islets was compared with that of islets incubated in γ-globulin isolated from nonimmune serum. Islets incubated in antisomatostatin γ-globulin released significantly more insulin at 4, 8,16, and 32 mM glucose and significantly more glucagon at 8,16, and 32 mM glucose, P < 0.05–0.005. For glucose-stimulated insulin release the threshold was decreased, the Vmax was increased, but the apparent Km was unaltered; for glucose-suppression of glucagon release the threshold was increased, maximal suppression was decreased, but the apparent Ki was unaltered. The augmentative effect of the antisomatostatin γ-globulin was most prominent at 4 mM glucose for insulin release and at 8 mM glucose for glucagon release, but was not limited to glucose since both insulin and glucagon release stimulated by arginine were also augmented by antisomatostatin γ-globulin. These results provide evidence that endogenous somatostatin may act as a physiologic local regulator of both insulin and glucagon secretion and that its effect on insulin and glucagon secretion is dependent on the prevailing glucose concentration.

SUMMARY To assess the relative contribution of overproduction and underutilization of glucose and ketone bodies to the development of diabetic ketoacidosis in man, the effects of acute insulin deficiency on glucose and ketone body turnovers were determined in seven ketosis-prone (type I) diabetic subjects. After termination of prolonged intravenous infusions of insulin, which had been maintaining the subjects euglycemic, plasma free insulin decreased from 18 ± 4 μU/ml to 7 ± 1 μU/ml, P < 0.01; plasma glucagon increased from 67 ± 6 pg/ml to 259 ± 67 pg/ml, P < 0.05, but plasma growth hormone and cortisol did not increase. Plasma glucose increased from 5.4 ± 0.3 mM to 15.6 ± 1.0 mM, P < 0.01; plasma ketone bodies (β-hydroxybutyrate plus acetoacetate) increased from 1.4 ± 0.4 mM to 7.2 ± 1.5 mM, P < 0.01. Glucose production increased abruptly from 13.2 ± 1.1 μmol/kgmin to a maximum of 26.1 ± 2.9 μmol/kg-min at 2 h but then decreased toward baseline rates; glucose utilization also increased transiently. In contrast, both ketone body production and utilization increased progressively throughout the study from 5.4 ± 1.4 and 5.5 ± 1.1 to 18.3 ± 3.9 and 14.7 ± 2.1 μmol/kg-min, respectively, P < 0.01. Clearance of both glucose and ketone bodies decreased more than 50%, P < 0.01. These results indicate that overproduction of glucose and ketone bodies is the primary process involved in the initiation of diabetic ketoacidosis in man. However, persistent overproduction of glucose and ketone bodies may not be necessary for the maintenance of hyperglycemia and hyperketonemia, since clearance of both substrates is impaired. Finally, since, of all counter-insulin hormones measured, only plasma glucagon increased coincident with increases in glucose and ketone body production, these results provide further evidence that glucagon may be the most important counter-insulin hormone involved in the genesis Of ketoacidosis.

The responses of glucagon, growth hormone, and insulin secretion to the oral administration of glucose and to the intravenous infusion of saline, arginine, and insulin were measured in seven patients who had stable diabetes, eight who had unstable diabetes, and seven healthy volunteers. Hyperglycemia suppressed secretion of glucagon in normal subjects but not in diabetics. The oral glucose and arginine infusion tests demonstrated partial preservation of insulin-secretory ability in stable diabetics and its virtual absence in unstable diabetics. Glucagon responses to arginine infusion were similar in all three groups. In response to hypoglycemia induced by insulin infusion, the concentrations of plasma glucagon increased in normal subjects and, to a lesser extent, in stable diabetics but increased in only two of the unstable diabetics. The impairment in glucagon response during hypoglycemia in diabetics correlated positively with the degree of diabetic instability and insulin deficiency during glucose and arginine testing. The severity of the insulin deficiency also correlated with the degree of diabetic instability. These findings support the hypothesis that inherent abnormalities of insulin and glucagon secretion may account for many of the clinical characteristics of unstable and stable diabetic patients.

The incidence and prevalence of diabetes mellitus in residents of Rochester, Minnesota, for 25 years (1945 to 1970) were determined from available medical records. The over-all incidence rate for diabetes is 133 new cases per 100,000 population per year (age-adjusted to 1970 U.S. white population). The rate increased with age for both men and women and was higher among men over 30 years of age. The average annual incidence rates per five-year period for juvenile-onset diabetes mellitus were low and variable and showed little change. Polyuria, polydipsia, glycosuria, lean habitus, loss of weight, and high levels of fasting hyperglycemia at initial diagnosis occurred more frequently in younger than in older patients. The peak incidence in 1960 through 1964 and the decrease in the following five years may be a reflection of the introduction of the AutoAnalyzer method for blood glucose in 1958. The average annual incidence rates for 1955 through 1959 and 1965 through 1969 were essentially the same. The over-all prevalence for diabetes mellitus is 1.6 per cent, with a higher rate among men than among women over 40 years of age; among school children the rate is 0.1 per cent. Survivorship in the diabetic population is lower than that in the general population. The leading cause of death was coronary heart disease, the death rate from it being higher than for the general population.

Excess free fatty acid release (rate of appearance) is seen in overnight postabsorptive, upper body obese women and, if present postprandially, could contribute to glucose intolerance. These studies examine the antilipolytic effect of a mixed meal in upper body obese, lower body obese, and nonobese women and the contribution of meal triglyceride fatty acids to circulating free fatty acids. Eight upper body obese, 8 lower body obese, and 8 nonobese age-matched, premenopausal women were studied. Systemic oleate Ra ([3H]oleate) was measured before and after an evening meal that contained triolein labeled with [14C]triolein as the only source of fat. Premeal oleate Ra was greater in both upper body obese and lower body obese women than nonobese women. The nadir of total oleate Ra occurred 90–240 min postprandially and was less (P < 0.01) in nonobese and lower body obese women (63 ± 10 and 87 ± 17 μmol/min) than in upper body obese women (140 ± 21 μmol/min). Meal oleate Ra contributed substantially to total oleate Ra. The nadir for endogenous oleate Ra in nonobese and lower body obese women was less (P < 0.01) than that observed in upper body obese women. We conclude that the antilipolytic effect of a mixed meal is reduced in upper body obese women and that meal triglyceride fatty acids contribute significantly to postprandial free fatty acid flux.