Biomedical subjects

A Giacca

Publications and source records attributed to A Giacca.

At least 19 recordsLinked to original sources

PubMed2001

Low-dose IGF-I has no selective advantage over insulin in regulating glucose metabolism in hyperglycemic depancreatized dogs.

At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 microg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 microg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67.8 microg/kg, i.e. 29.1 microg/kg bolus plus 0.215 microg/kg( )per min infusion; n=5) or insulin 49.5 mU/kg (9 mU/kg bolus plus 0.45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54+/-3 and 56+/-2% s.e. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5.2+/-0.2, insulin 5.5+/-0.3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and beta-hydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 1 diabetes mellitus.

3-Hydroxybutyric Acid↗

PubMed2000

Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats.

We have previously shown that chronic insulin treatment by the intraperitoneal route normalizes the elevated glucose production (GP) in streptozotocin (STZ) diabetic rats, while insulin delivered by the subcutaneous route only partially normalizes GP. To investigate the biochemical mechanism of the effect of chronic insulin delivery by either route on hepatic glucose metabolism, we measured the hepatic activity of glucose 6-phosphatase (G6Pase) and glucokinase (GK). Four groups of rats were used: (1) nondiabetic rats (N, n = 7), (2) untreated STZ diabetic rats (D, n = 8), (3) diabetic rats treated intraperitoneally (IP, n = 6), or (4) subcutaneously (SC, n = 8) (both 3 U of insulin/d). Glucose levels, higher in D, were normalized by insulin treatment regardless of route. Peripheral insulin levels were lowest in D and highest in SC as expected (N, 162 +/- 18 pmol/L; D, 66 +/- 12; IP, 360 +/- 96; SC, 798 +/- 198). STZ diabetes resulted in a 10-fold decrease in GK (P < .001), and a 2-fold increase in G6Pase activity (P < .01). Both intraperitoneal and subcutaneous treatments normalized G6Pase activity. In contrast, with subcutaneous but not intraperitoneal treatment, GK activity was still 35% less than normal (SC v N, P < .05). Glucose 6-phosphate (G6P) levels did not differ among the groups. In summary: (1) the increase in GP in D reflected increased activity of G6Pase and reduced activity of GK, (2) the partial suppression of GP with subcutaneous insulin treatment reflected correction of increased G6Pase activity, but only partial correction of low GK activity, and (3) the normalization of GP with intraperitoneal insulin treatment reflected correction of both increased G6Pase activity and low GK activity. Our current studies indicate that chronic intraperitoneal insulin treatment is superior to subcutaneous treatment with regard to hepatic glucose metabolism.

Animals↗

PubMed2000

Effect of JTT-501 on net hepatic glucose balance and peripheral glucose uptake in alloxan-induced diabetic dogs.

JTT-501, a new insulin sensitizer, improves peripheral glucose uptake in insulin-resistant animals such as KK-Ay mice and Zucker fatty rats. However, the effect of JTT-501 on hepatic glucose metabolism has not been addressed. To investigate this effect, experiments were performed on 6 alloxan-diabetic dogs. Three experiments were conducted for each dog: the treatment experiment, which followed a 10-day oral treatment with JTT-501 30 mg x kg(-1) x d(-1), and 2 control experiments 2 weeks before and 2 weeks after the treatment experiment. A hyperinsulinemic-hyperglycemic clamp was performed with the tracer dilution method (intraportal insulin infusion rate, 18 pmol x kg(-1) x min(-1)). Arterial hyperglycemia (approximately 10 mmol/L) was maintained by adjusting the peripheral glucose infusion rate. After a 45-minute basal period (period I), portal glucose infusion (22.2 micromol x kg(-1)min(-1)) was administered for 120 minutes (period II). This was followed by a 90-minutes recovery period (period III). JTT-501 increased insulin-stimulated glucose utilization (P < .05) and enhanced insulin-mediated suppression of glucose production (P < .05) in periods I and III. Net hepatic glucose balance (NHGB) determined by the arterial-venous (A-V) difference method was increased by JTT-501 in period II (P < .01). We conclude that JTT-501 enhances both hepatic and peripheral insulin sensitivity and therefore may have important therapeutic effects in type 2 diabetes.

Alloxan↗

PubMed2000

Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment.

The study aim was to investigate the effect of the route of insulin treatment on the glucagon and glucose production (GP) responses to hypoglycemia in the diabetic rat. Experiments were performed in 4 groups of rats: (1) streptozotocin (STZ)-induced diabetic, untreated (D, n = 7), (2) diabetic treated with subcutaneous insulin (DSC, n = 8), (3) diabetic treated with intraperitoneal insulin (DIP, n = 6), and (4) normal control (N, n = 10). Slow-release insulin implants were used in DSC and DIP rats for 10 to 14 days (3 U/d). A hyperinsulinemic (120 pmol x kg(-1) x min(-1) insulin)-hypoglycemic (glycemia = 2.5 +/- 0.1 mmol/L) clamp following an isoglycemic basal period was performed in 5-hour fasted rats. Basal plasma glucose was normalized in both DSC and DIP rats; however, in DSC but not DIP rats, glucose normalization required peripheral hyperinsulinemia. Tracer-determined GP, which was elevated in D rats, was completely normalized in DIP but only partially corrected in DSC rats. Basal glucagon levels were similar in all groups. During hypoglycemia, GP was suppressed in D rats (delta, -28.9 +/- 5.0 micromol x kg(-1) x min(-1), moderately increased in DSC rats (delta, 6.1 +/- 5.6, P < .01 v D), but markedly increased in DIP and N rats (delta, 34.5 +/- 4.5 for DIP and 16.8 +/- 2.8 for N; P < .01 vD, P < .05 for DIP v DSC or N). Plasma glucagon increased 6-fold in N (945 +/- 129 pg/mL), only doubled in D (424 +/- 54), and tripled in DSC (588 +/- 83), but increased 5-fold in DIP rats (1,031 +/- 75, P < .05 v D and DSC). We conclude that in STZ-diabetic rats, (1) intraperitoneal but not subcutaneous insulin treatment normalizes basal GP, and (2) intraperitoneal insulin treatment as compared with subcutaneous treatment alleviates peripheral hyperinsulinemia and results in increased glucagon and GP responses to hypoglycemia.

Animals↗

PubMed2000

Mechanisms linking diet and colorectal cancer: the possible role of insulin resistance.

Diet is clearly implicated in the origin of colorectal cancer, with risk factors for the disease including reduced consumption of vegetables, fiber, and starch and increased consumption of red meat and animal fat. Several hypotheses have been developed to explain these associations. Most recently, McKeown-Eyssen and Giovannucci noted the similarity of the risk factors for colorectal cancer and those for insulin resistance and suggested that insulin resistance leads to colorectal cancer through the growth-promoting effect of elevated levels of insulin, glucose, or triglycerides. We briefly review the evidence from observational, epidemiological, and experimental animal studies linking diet with insulin resistance and colorectal cancer. The evidence suggests that diets high in energy and saturated fat and with high glycemic index carbohydrate and low levels of fiber and n-3 fatty acids lead to insulin resistance with hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. We then consider how insulin, the related insulin-like growth factors, triglycerides, and nonesterified fatty acids could lead to increased growth of colon cancer precursor lesions and the development of colorectal cancer. Finally, we consider the implications of this scheme on possible future research directions, including studies of satiety and clinical tests of the importance of insulin resistance in the colon carcinogenesis process.

Animals↗

PubMed2000

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the FFA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with type 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of beta-cell failure in obese individuals who are at risk for developing type 2 diabetes. They do not, however, seem to further deteriorate the beta-cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group.

Adult↗

PubMed2000

Possible mechanisms relating diet and risk of colon cancer.

Two recent developments in cancer epidemiology and experimental carcinogenesis provide the basis for two possible mechanisms relating diet and colon cancer risk. The first development is the accumulating epidemiological evidence for an association between insulin resistance and colonic adenomas and cancers. This evidence suggests the following mechanism: the consumption of excess dietary energy results in the development of insulin resistance with increased circulating levels of insulin, triglycerides, and non-esterified fatty acids. These circulating factors subject colonic epithelial cells to a proliferative stimulus and also expose them to reactive oxygen intermediates. These long-term exposures result in the promotion of colon cancer. The second development is the continuing identification of agents that significantly inhibit experimental colon carcinogenesis. These observations suggest the following mechanism: focal loss of epithelial barrier function resulting from a failure of terminal differentiation results in the "leak" of a presently undefined toxin and a focal inflammatory response characterized by evidence of the activation of the COX-2 enzyme and an oxidative stress with the release of reactive oxygen intermediates. The resulting focal proliferation and mutagenesis give rise to aberrant crypt foci and adenomas. The process is inhibited by: (a) demulcents confined to the colonic lumen that "repair" the surface; (b) anti-inflammatory agents; or (c) antioxidants. The two mechanisms, i.e., insulin resistance acting throughout the body and focal epithelial barrier failure acting locally, can describe most of the known relationships between diet and colon cancer risk.

Carcinogens↗

PubMed1999

Increased dependence of glucose production on peripheral insulin in diabetic depancreatized dogs.

We have recently found that in nondiabetic dogs and humans, suppression of glucose production (GP) is mediated by both peripheral and hepatic effects of insulin. We have also found that both nonesterified fatty acids (NEFA) and glucagon are important determinants of the peripheral effect of insulin on GP. However, in moderately hyperglycemic depancreatized dogs, suppression of GP appeared to be mediated by peripheral but not hepatic insulin. In this latter study, insulin concentrations were in the high postprandial range (approximately 300 pmol/L) and suppression of GP may have been close to maximum. The aim of the present study was to determine whether GP can be regulated by hepatic insulin in depancreatized dogs at low insulin concentrations in the postabsorptive range. Depancreatized dogs were maintained at moderately hyperglycemic levels (approximately 10 mmol/L) by subbasal insulin infusions. In paired experiments, additional low-dose equimolar insulin infusions (0.75 pmol/kg x min) were administered peripherally (PER, n = 6) or portally (POR, n = 6) during glucose clamps. This resulted in a minimal increase in peripheral insulin levels, which was greater in PER versus POR, 29.0 +/- 3.7 versus 11.7 +/- 2.2 pmol/L. Also, we infused insulin peripherally at half this rate (1/2 PER, n = 6) to match the increase in peripheral insulin levels in POR (1/2 PER, 14.6 +/- 2.2) and thus obtain a selective POR versus 1/2 PER difference in hepatic sinusoidal insulin levels. PER suppressed GP more than POR (45.4% +/- 4.0% v 35.3% +/- 6.8%, P < .001), whereas POR did not suppress GP more than 1/2 PER (35.6% +/- 6.3%). Therefore, suppression of GP was proportional to peripheral rather than hepatic sinusoidal insulin levels, as in our previous study at higher insulin concentrations. In conclusion, during glucose clamps in moderately hyperglycemic depancreatized dogs, (1) suppression of GP was dominated by insulin's peripheral effects not only at postprandial but also postabsorptive insulin levels, and (2) we found no evidence for a hepatic effect of insulin in suppressing GP. We hypothesize that this effect is reduced in the depancreatized dog model of diabetes due to hepatic insulin resistance and/or hyperglycemia.

Alanine↗

PubMed1999

Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation.

The in vivo effect of elevated free fatty acids (FFA) on beta-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, approximately 10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (SI) was lower, and disposition index (DI = insulin sensitivity x insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 +/- 1.4 x 10(-3) l2. kg-1. min-2 in control vs. 10.0 +/- 1.9 x 10(-3) l2. kg-1. min-2 with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 +/- 1.2 x 10(-3) l2. kg-1. min-2 in control vs. 6.1 +/- 0.7 x 10(-3) l2. kg-1. min-2 with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this beta-cell compensation.

Adult↗

PubMed1999

Counterregulatory response to hypoglycemia differs according to the insulin delivery route, but does not affect glucose production in normal humans.

The magnitude of the counterregulatory response to insulin-induced hypoglycemia is primarily determined by the degree of hypoglycemia. We examined whether the route of acute insulin delivery (portal or peripheral venous) is also important in determining the magnitude of the counterregulatory response to hypoglycemia in nine healthy nondiabetic men. Pancreatic insulin secretion, stimulated by an i.v. tolbutamide infusion (portal insulin study), was matched with an exogenous insulin infusion into the peripheral vein 4-6 weeks later (peripheral insulin study). Each study consisted of a 150-min baseline tracer equilibration period, a 180-min euglycemic hyperinsulinemic (portal or peripheral insulin delivery) period, a 60-min hypoglycemic period in which insulin secretion diminished during tolbutamide or was reduced during exogenous insulin, and a 30-min recovery period. Peripheral venous glucose concentrations were well matched in the portal and peripheral studies during euglycemia and hypoglycemia (glucose nadir, 2.9 +/- 0.1 mmol/L in the portal and 2.7 +/- 0.1 mmol/L in the peripheral; mean +/- SEM; P = NS), and insulin concentrations were about 1.5-fold higher throughout the experiment in the peripheral vs. the portal insulin study due to the first pass extraction of insulin in the portal study. There was a much greater increment (P < 0.0001) in FFA in the portal vs. the peripheral study (area under the curve: portal, 19.5 +/- 3.9 mmol/L x 90 min; peripheral, 3.3 +/- 1.1 mmol/L x 90 min), whereas plasma glucagon and GH were higher in the peripheral study (P = 0.01 for glucagon; P = 0.015 for GH). There was no significant difference between studies in epinephrine and norepinephrine responses to hypoglycemia or stimulation of endogenous glucose production (area under the curve: portal, 636 +/- 103 micromol/kg x 90 min; peripheral, 705 +/- 69 micromol/kg x 90 min; P = NS). In summary, we have shown that the glucagon, GH, and FFA responses to hypoglycemia during insulin dissipation are affected by the route of insulin delivery and are not controlled exclusively by the nadir blood glucose level. The clinical importance of these observations in diabetic subjects as they relate to route of insulin delivery (portal or peripheral) during insulin dissipation remains to be determined.

Adult↗

PubMed1999

Prolonged elevation of plasma free fatty acids desensitizes the insulin secretory response to glucose in vivo in rats.

Prolonged exposure of pancreatic islets to free fatty acids (FFAs) inhibits glucose-stimulated insulin secretion (GSIS) in vitro. However, FFA inhibition of GSIS has not been clearly demonstrated in vivo. We examined the in vivo effect of prolonged elevation of plasma FFAs on GSIS using a two-step hyperglycemic clamp in rats treated with a 48-h intravenous infusion of either 20% Intralipid plus heparin (INT) (5 microl/min plus heparin, 0.1 U/min; n = 8), oleate (OLE) (1.3 microEq/min; n = 6), saline (SAL) (n = 6), or bovine serum albumin (BSA) (vehicle for OLE; n = 5). Because there was no difference in any of the parameters between BSA and SAL rats, these groups were combined as control rats (CONT) (n = 11). At the end of the 48-h OLE/INT/CONT infusions, after an overnight fast, plasma glucose was clamped for 2 h at 13 mmol/l and for another 2 h at 22 mmol/l. Preclamp plasma FFAs were elevated twofold (P < 0.01) versus CONT with both INT and OLE (NS, INT vs. OLE). Preclamp glucose, insulin, and C-peptide levels were higher in INT than in CONT rats (P < 0.05), suggesting insulin resistance, but they were not different in OLE and CONT rats. The insulin and C-peptide responses to the rise in plasma glucose from basal to 13 mmol/l were lower in OLE (336 +/- 72 pmol/l and 1.2 +/- 0.1 nmol/l, P < 0.01 and P < 0.05, respectively) than in CONT (552 +/- 54 and 1.9 +/- 0.1) rats, but they were not different between CONT and INT rats (648 +/- 150 and 2.0 +/- 0.4). The insulin and C-peptide responses to the rise in plasma glucose from 13 to 22 mmol/l were lower in both INT (1,188 +/- 204 pmol/l and 3.0 +/- 0.3 nmol/l, P < 0.01 and P < 0.001) and OLE (432 +/- 60 and 1.7 +/- 0.2, P < 0.001 vs. CONT or INT) rats than in CONT rats (1,662 +/- 174 and 5.0 +/- 0.6). In summary, 1) both INT and OLE decreased GSIS in vivo in rats, and 2) the impairing effect of INT on GSIS was less than that of OLE, which might be due to the different type of fatty acid (mostly polyunsaturated in INT versus monounsaturated as OLE) and/or to differential effects of INT and OLE on insulin sensitivity. In conclusion, prolonged elevation of plasma FFAs can desensitize the insulin secretory response to glucose in vivo, thus inducing a beta-cell defect that is similar to that found in type 2 diabetes.

Animals↗

PubMed1999

Resistance to insulin's acute direct hepatic effect in suppressing steady-state glucose production in individuals with type 2 diabetes.

We and others have shown that insulin acutely suppresses glucose production in fasting nondiabetic humans and dogs, by both a direct hepatic effect and an indirect (extrahepatic) effect, and in diabetic dogs by an indirect effect alone. In type 2 diabetes, there is resistance to insulin's ability to suppress hepatic glucose production, but it has not previously been determined whether the resistance is primarily at the level of the hepatocyte or the peripheral tissues. To determine whether the diabetic state reduces the direct effect of insulin in humans, we studied nine patients with untreated type 2 diabetes who underwent three studies each, 4-6 weeks apart. 1) Portal study (POR): intravenous tolbutamide was infused for 3 h with calculation of pancreatic insulin secretion from peripheral plasma C-peptide. 2) Peripheral study (PER): equidose insulin was infused by peripheral vein. 3) Half-dose peripheral insulin study (1/2 PER): matched peripheral insulin levels with study 1. In all studies, glucose was clamped at euglycemia, glucose turnover was measured with the constant specific activity method, and 3-[3H]glucose was purified by high-performance liquid chromatography. Peripheral insulin was lower in POR versus PER but slightly higher in POR versus 1/2 PER, although most of the difference could be accounted for by higher proinsulin levels in POR (stimulated by tolbutamide). Calculated portal insulin was approximately 1.3-fold higher in POR versus PER and approximately 2.2-fold higher in POR versus 1/2 PER. In the final 30 min of the clamp, glucose production reached a lower steady-state level in PER than in POR (4.0 +/- 0.4 vs. 5.3 +/- 0.5 pmol(-1) x kg(-1) x min(-1), P < 0.05), despite the higher hepatic insulin level in POR. In contrast with our studies in nondiabetic individuals, glucose production was not more suppressed at steady state in POR versus 1/2 PER (5.3 +/- 0.4 micromol x kg(-1) x min(-1)), despite much higher hepatic insulin levels in POR. In conclusion, this is the first study in patients with type 2 diabetes to characterize insulin resistance to the acute direct suppressive effect of insulin on hepatic glucose production.

Adult↗

PubMed1999

Free fatty acids impair hepatic insulin extraction in vivo.

Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol x kg(-1) x min(-1) for 150 min (period A, high insulin dose), and then at 2.4 pmol x kg(-1) x min(-1) for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol x kg(-1) x min(-1) for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 +/- 167, 1,491 +/- 240, 1,159 +/- 221 micromol/l (IH) and 221 +/- 44, 329 +/- 72, 176 +/- 44 micromol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 +/- 114, 126 +/- 12, 1,050 +/- 72 pmol/l for IH vs. 1,344 +/- 168, 96 +/- 4.2, 882 +/- 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E(H) were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 +/- 0.6, 12.0 +/- 0.9, 10.2 +/- 0.6 ml x kg(-1) x min(-1)) than with SAL (11.2 +/- 1, 13.6 +/- 0.7, 11.9 +/- 0.9 ml x kg(-1) x min(-1)) in periods A, B, and C. E(H) was also lower (P < 0.05) with IH (25 +/- 4, 40 +/- 5, 32 +/- 5%) than with SAL (30 +/- 2.8, 47 +/- 3, 38 +/- 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity.

Animals↗

PubMed1999

Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs.

To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to stimulating insulin secretion, we studied totally depancreatized dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 microg x kg(-1) x min(-1)) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng x kg(-1) x min(-1)). To simulate the residual intraportal insulin secretion in type 2 diabetes, basal intraportal insulin infusion was given to obtain plasma glucose concentrations of approximately 10 mmol/l. Glucose was clamped at this level for the remainder of the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol x kg(-1) x min(-1), or low dose, 0.75 pmol x kg(-1) x min(-1)) with or without GLP-1(7-36) amide (1.5 pmol x kg(-1) x min(-1)). Glucose production and utilization were measured with 3-[3H]glucose, using radiolabeled glucose infusates. In 12 paired experiments with six dogs at the high insulin dose, GLP-1 infusion resulted in higher glucose requirements than saline (60.9+/-11.0 vs. 43.6+/-8.3 micromol x kg(-1) x min(-1), P< 0.001), because of greater glucose utilization (72.6+/-11.0 vs. 56.8+/-9.7 micromol x kg(-1) x min(-1), P<0.001), whereas the suppression of glucose production was not affected by GLP-1. Free fatty acids (FFAs) were significantly lower with GLP-1 than saline (375.3+/-103.0 vs. 524.4+/-101.1 micromol/l, P<0.01), as was glycerol (77.9+/-17.5 vs. 125.6+/-51.8 micromol/l, P<0.05). GLP-1 receptor gene expression was found using reverse transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression were also found in adipose tissue using Northern blotting. In 10 paired experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect glucose utilization or FFA and glycerol suppression when compared with saline, suggesting that GLP-1's effect on insulin action was dependent on the insulin dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated glucose utilization, an effect that might be contributed in part by GLP-1 potentiation of insulin's antilipolytic action.

Adipose Tissue↗

PubMed1998

Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Adult↗

PubMed1998

Insulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs.

To determine whether the predominant effect of insulin in suppressing tracer-determined glucose production (Ra) is hepatic or peripheral, we infused insulin peripherally (PER) and portally (POR) at both low (0.75 pmol.kg-1.min-1) and high physiological rates (2.7 pmol.kg-1.min-1) during euglycemic clamps in normal dogs. We also infused insulin peripherally at one-half these rates (1/2 PER) to match the peripheral insulin levels in POR and thus obtain a selective POR vs. 1/2 PER difference in hepatic insulin levels. At the high-rate insulin infusion, peripheral insulin levels were greatest with PER (PER = 212 +/- 10 pM, n = 5; POR = 119 +/- 5 pM, n = 6; 1/2 PER = 122 +/- 5 pM, n = 6). Calculated hepatic insulin levels were greatest with POR (POR = 227 +/- 13 pM, PER = 206 +/- 19 pM, 1/2 PER = 123 +/- 8 pM). High-dose PER yielded a greater suppression of Ra than POR (79 +/- 18 vs. 56 +/- 6%, P < .001). Ra was only suppressed by 45 +/- 6% with 1/2 PER (P < 0.01 vs. POR on 6 paired experiments). Free fatty acid (FFA) was suppressed by 57 +/- 8% with PER and only by 33 +/- 5 and 37 +/- 2% with POR and 1/2 PER, respectively. The low-dose PER and POR yielded an equal Ra suppression (PER = 46 +/- 9%, POR = 43 +/- 4%). Only 1/2 PER was associated with a lower suppression of Ra (36 +/- 8, P < 0.05 vs. POR). FFA showed similar suppression in all three groups (approximately 25%). Using both insulin infusion rates, the percent Ra suppression per unit difference in peripheral insulin was approximately twofold greater than that per unit difference in hepatic insulin. These results suggest that, during euglycemic clamps without somatostatin in normal dogs, Ra suppression is mediated by both peripheral and hepatic effects of insulin and that peripheral insulin, at least at high physiological infusion rates, is more potent than hepatic insulin in suppressing Ra.

Animals↗

PubMed1998

Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans.

We have shown previously that the greater suppression of endogenous glucose production (GP) with equimolar peripheral vs. portal insulin cannot be detected or is minimally reversed when the insulin-induced suppression of either free fatty acids (FFA) or glucagon alone is prevented. The present experiments were designed to minimize the insulin suppression of both glucagon and FFA in an attempt to further examine the mechanism of insulin's peripheral effect on GP. In nine healthy men, we investigated the effect of limiting the insulin suppression of both FFA and glucagon by infusing heparin (250 U/h), Intralipid 10% (25 ml/h), and glucagon (0.65 ng . kg-1 . min-1) during 1) portal (n = 9), 2) equimolar peripheral (n = 9), and 3) half-dose peripheral insulin delivery (n = 4) by use of our previously published tolbutamide infusion method, with calculation and matching of insulin secretion rate. GP decreased by 57.2 +/- 2. 6% with portal, 39.0 +/- 4.1% with equimolar peripheral, and 31.5 +/- 2.7% with half-dose peripheral insulin delivery (P < 0.001 for portal vs. peripheral and P < 0.001 for portal vs. half-dose peripheral). In contrast, in six control subjects in whom glucagon and FFA were not replaced, GP decreased by 62.6 +/- 2.4% with portal (n = 6), 75.7 +/- 3.0% with peripheral (n = 6), and 56.3 +/- 3.0% with half-dose peripheral (n = 4) insulin delivery (P < 0.01 for portal vs. peripheral and P = not significant for portal vs. half-dose peripheral). In summary, the greater suppression of GP with equimolar peripheral vs. portal insulin is eliminated and markedly reversed if the acute insulin-induced suppression of both plasma FFA and glucagon is minimized. This suggests that the insulin-induced suppression of glucagon and FFA has additive or cooperative effects in mediating the acute extrahepatic effect of insulin on GP.

Adult↗

PubMed1998

Glucose production, utilization, and cycling in response to moderate exercise in obese subjects with type 2 diabetes and mild hyperglycemia.

The glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.

Adult↗