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Biomedical subjects

A Giacca

Publications and source records attributed to A Giacca.

At least 19 recordsLinked to original sources
PubMed2006

Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans.

AIMS/HYPOTHESIS: Prolonged elevation of plasma specific fatty acids may exert differential effects on glucose-stimulated insulin secretion (GSIS), insulin sensitivity and clearance. SUBJECTS AND METHODS: We examined the effect of oral ingestion, at regular intervals for 24 h, of an emulsion containing either predominantly monounsaturated (MUFA), polyunsaturated (PUFA) or saturated (SFA) fat or water (control) on GSIS, insulin sensitivity and insulin clearance in seven overweight or obese, non-diabetic humans. Four studies were conducted in each individual in random order, 4-6 weeks apart. Twenty-four hours after initiation of oral ingestion, subjects underwent a 2 h, 20 mmol/l hyperglycaemic clamp to assess GSIS, insulin sensitivity and insulin clearance. RESULTS: Following oral ingestion of any of the three fat emulsions over 24 h, plasma NEFAs were elevated by approximately 1.5- to 2-fold over the basal level. Ingestion of any of the three fat emulsions resulted in reduction in insulin clearance, and SFA ingestion reduced insulin sensitivity. PUFA ingestion was associated with an absolute reduction in GSIS, whereas insulin secretion failed to compensate for insulin resistance in subjects who ingested SFA. CONCLUSIONS/INTERPRETATION: Oral ingestion of fats with differing degrees of saturation resulted in different effects on insulin secretion and action. PUFA ingestion resulted in an absolute reduction in insulin secretion and SFA ingestion induced insulin resistance. Failure of insulin secretion to compensate for insulin resistance implies impaired beta cell function in the SFA study.

Adult↗
PubMed2005

A pilot randomised controlled trial to reduce colorectal cancer risk markers associated with B-vitamin deficiency, insulin resistance and colonic inflammation.

Colorectal cancer risk is associated with biochemical markers for B-vitamin deficiency, insulin resistance and colonic inflammation, suggesting that these three conditions are each involved in colon carcinogenesis. We expected that dietary supplements of folic acid, n-3 fatty acids and calcium would reduce the markers and thus possibly cancer risk. We therefore randomised 98 participants, with previous colonic polyps or intramucosal carcinomas, to a combined treatment of supplementary folic acid, fish oil and calcium carbonate, or placebos for 28 days. Blood and faecal samples were obtained prior to and at the conclusion of the intervention and analysed for plasma folate, homocysteine, insulin, free fatty acids, triglycerides and faecal calprotectin. In addition, plasma vitamin B12, thiamin, glucose and C-reactive protein were assessed. Our supplemental strategy modestly affected some of the biomarkers associated with folate metabolism and insulin resistance, but had no effect on those associated with colonic inflammation. This pilot study demonstrates the feasibility and practicality of clinical trials aimed at reducing diet-related biochemical risk markers for colon cancer. We suggest that long-term intervention studies with tumour-related end points should be undertaken when the intervention agents used are found effective in short-term biochemical risk marker trials.

Adenoma↗
PubMed2004

Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men.

AIMS/HYPOTHESIS: A prolonged increase of plasma NEFA impairs acute glucose-stimulated insulin secretion (GSIS) in vitro and in vivo. Our study therefore examined the combined effect of increased plasma NEFA and glucose on GSIS in humans. METHODS: We examined GSIS on four occasions in eight obese men during a 10 mmol/l hyperglycaemic clamp and after a 24-h infusion of (i) normal saline, (ii) intralipid and heparin to raise plasma NEFA about two-fold above basal, (iii) 20% dextrose to raise plasma glucose to about 7.5 mmol/l and (iv) intralipid and heparin combined with 20% dextrose to raise plasma NEFA and glucose. RESULTS: In study (iii) insulin sensitivity was about 20% greater than in study (i) and the disposition index was about 50% higher. Insulin sensitivity tended to be lower in study (ii) whereas the disposition index was lower than in study (i), confirming previous observations. The combination of increased plasma NEFA and glucose (study iv) reduced insulin sensitivity in comparison with study (i) and completely abolished the increase in insulin sensitivity and disposition index seen in study (iii), but did not reduce the latter to a lower value than that in the saline control study (study i). CONCLUSIONS/INTERPRETATION: We showed that a prolonged increase of plasma NEFA completely abolishes the stimulatory effect of moderate hyperglycaemia on insulin sensitivity and beta-cell function in obese humans. This suggests that previous observations, showing that a prolonged increase of plasma NEFA impairs pancreatic beta-cell function, also apply to the hyperglycaemic state.

Blood Glucose↗
PubMed2001

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans.

AIMS/HYPOTHESIS: We have shown previously that the increase of plasma non-esterified fatty acids for 48 h results in decreased glucose-stimulated insulin secretion in lean and non-diabetic obese subjects. It is currently not known if a prolonged increase in non-esterified fatty acids also impairs the insulin secretory response to non-glucose secretagogues. METHODS: Heparin and intralipid (to increase plasma non-esterified fatty acid concentrations by about two- to fourfold) or normal saline was infused intravenously for 48 h in 14 non-diabetic obese subjects. On the third day in both studies, insulin, C-peptide, proinsulin, and insulin secretion rate were assessed in response to an intravenous arginine infusion at fasting glucose concentration and a second arginine infusion after a 60-min 11 mmol/l hyperglycaemic clamp. RESULTS: There were no significant differences detected in acute (5 min) or total (90 min) arginine-stimulated C-peptide or insulin secretion response in the heparin-intralipid study compared with the control group at fasting glucose or during hyperglycaemia. CONCLUSION/INTERPRETATION: We have shown that a prolonged increase in plasma NEFA does not blunt arginine-stimulated insulin secretion or plasma insulin concentrations in non-diabetic obese subjects. These findings suggest that the previously demonstrated NEFA-induced impairment in insulin secretory response to glucose cannot be generalized for non-glucose secretagogues.

Adult↗
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↗
PubMed2001

The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism.

Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n = 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n = 7) and healthy control subjects (n = 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite approximately 35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization during the euglycemic-hyperinsulinemic clamp was approximately 40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an approximately 50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no elevation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.

Adult↗
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↗