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OBJECTIVE--To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action. RESEARCH DESIGN AND METHODS--Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 rag) for 4 months. RESULTS--Glucose was clamped before and after therapy at ∼5 mmol/l, insulin raised to ∼180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at ∼75 pg/ml, and glycerol maintained at ∼200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 ± 3 vs. 24 ± 2 µmol ⋅ kg-1 ⋅ min-1) or metformin (22 ± 2 vs. 24 ± 3 µmol ⋅ kg-1 ⋅ min-1). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 ± 1.0 vs. 0.2 ± 1.6 µmol ⋅ kg-1 ⋅ min-1) and gluconeogenesis (n = 11; 4.5 ± 0.9 vs. 0.8 ± 1.2 µmol ⋅ kg-1 ⋅ min-1. Metformin did not alter either suppression of glucose production (5.8 ± 1.0 vs. 5.0 ± 0.8 µmol ⋅ kg-1 ⋅ min-1) or gluconeogenesis (n = 9; 3.7 ± 0.8 vs. 2.6 ± 0.7 µmol ⋅ kg-1 ⋅ min-1). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 ± 0.03 vs. 0.06 ± 0.01 mmol/l) but unchanged with metformin (0.12 ± 0.03 vs. 0.15 ± 0.07 mmol/l). CONCLUSIONS--Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake. Diabetes 57: 24-31, 2008 [ABSTRACT FROM AUTHOR]

To determine the mechanism(s) by which insulin inhibits endogenous glucose production (EGP) in nondiabetic humans, insulin was infused at rates of 0.25, 0.375, or 0.5 mU. kg(-1). min(-1) and glucose was clamped at approximately 5.5 mmol/l. EGP, gluconeogenesis, and uridine-diphosphoglucose (UDP)-glucose flux were measured using [3-(3)H]glucose, deuterated water, and the acetaminophen glucuronide methods, respectively. An increase in insulin from approximately 75 to approximately 100 to approximately 150 pmol/l ( approximately 12.5 to approximately 17 to approximately 25 microU/ml) resulted in progressive (ANOVA; P < 0.02) suppression of EGP (13.1 +/- 1.3 vs. 11.7 +/- 1.03 vs. 6.4 +/- 2.15 micromol x kg(-1) x min(-1)) that was entirely due to a progressive decrease (ANOVA; P < 0.05) in the contribution of glycogenolysis to EGP (4.7 +/- 1.7 vs. 3.4 +/- 1.2 vs. -2.1 +/- 1.3 micro mol x kg(-1) x min(-1)). In contrast, both the contribution of gluconeogenesis to EGP (8.4 +/- 1.0 vs. 8.3 +/- 1.1 vs. 8.5 +/- 1.3 micro mol x kg(-1) x min(-1)) and UDP-glucose flux (5.0 +/- 0.4 vs. 5.0 +/- 0.3 vs. 4.0 +/- 0.5 micro mol x kg(-1) x min(-1)) remained unchanged. The contribution of the direct (extracellular) pathway to UDP-glucose flux was minimal and constant during all insulin infusions. We conclude that higher insulin concentrations are required to suppress the contribution of gluconeogenesis of EGP than are required to suppress the contribution of glycogenolysis to EGP in healthy nondiabetic humans. Since suppression of glycogenolysis occurred without a decrease in UDP-glucose flux, this implies that insulin inhibits EGP, at least in part, by directing glucose-6-phosphate into glycogen rather than through the glucose-6-phosphatase pathway. [ABSTRACT FROM AUTHOR]

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at ∼8.3 mmol/l and insulin was increased to ∼300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 ± 2.6 vs. 650 ± 7.9 µmol · kg[sup -1] · min[sup -1]). Whole body glucose disappearance (37.0 ± 2.2 vs. 70.9 ± 8.7 µmol · kg[sup -1] · min[sup -1]; P < 0.001) and leg glucose uptake (24.3 ± 4.2 vs. 59.6 ± 10.0 µmol · kg fat-free mass of the leg[sup -1] · min[sup -1]; P < 0.02) were also lower, whereas splanchnic glucose production (8.2 ± 0.8 vs. 4.3 ± 0.7 µmol · kg[sup -1] · min[sup -1]; P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting wholebody glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production. [ABSTRACT FROM AUTHOR]

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to approximately 1 mmol/l by an 8-h Intralipid/heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match (n = 5, low glycerol) or double (n = 8, high glycerol) the plasma glycerol concentrations observed during the IL/Hep infusion. Glucose was clamped at approximately 8.3 mmol/l, and insulin was increased to approximately 300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. Leg glucose uptake (21.7 +/- 3.5 vs. 48.3 +/- 9.3 and 57.8 +/- 11.7 micromol x kg(-1) leg x min(-1)) was lower (P < 0.001) during IL/Hep than the low- or high-glycerol infusions, confirming that elevated FFAs caused insulin resistance in muscle. IL/Hep did not alter splanchnic glucose uptake or the contribution of the extracellular direct pathway to UDP-glucose flux. On the other hand, total UDP-glucose flux (13.2 +/- 1.7 and 12.5 +/- 1.0 vs. 8.1 +/- 0.5 micromol x kg(-1) x min(-1)) and flux via the indirect intracellular pathway (8.4 +/- 1.2 and 8.1 +/- 0.6 vs. 4.8 +/- 0.05 micromol x kg(-1) x min(-1)) were greater (P < 0.05) during both the IL/Hep and high-glycerol infusions than the low-glycerol infusion. In contrast, only IL/Hep increased (P < 0.05) splanchnic glucose production, indicating that elevated FFAs impaired the ability of the liver to autoregulate. Splanchnic insulin extraction, directly measured using the arterial and hepatic vein catheters, did not differ (67 +/- 3 vs. 71 +/- 5 vs. 69 +/- 1%) during IL/Hep and high- and low-glycerol infusions. We conclude that elevated FFAs exert multiple effects on glucose metabolism. They inhibit insulin- and glucose-induced stimulation of muscle glucose uptake and suppression of splanchnic glucose production. They increase the contribution of the indirect pathway to glycogen synthesis and impair hepatic autoregulation. On the other hand, they do not alter either splanchnic glucose uptake or splanchnic insulin extraction in nondiabetic humans. [ABSTRACT FROM AUTHOR]

We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 micromol. kg(-1). min(-1) while supplemental glucose was given intravenously to clamp glucose at approximately 10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at approximately 300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was approximately 35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Although it is well established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulator of insulin secretion, its effects on insulin action and glucose effectiveness are less clear. To determine whether GLP-1 increases insulin action and glucose effectiveness, subjects with type 2 diabetes were studied on two occasions. Insulin was infused during the night on both occasions to ensure that baseline glucose concentrations were comparable. On the morning of study, either GLP-1 (1.2 pmol x kg(-1) x min(-1)) or saline were infused along with somatostatin and replacement amounts of glucagon. Glucose also was infused in a pattern mimicking that typically observed after a carbohydrate meal. Insulin concentrations were either kept constant at basal levels (n = 6) or varied so as to create a prandial insulin profile (n = 6). The increase in glucose concentration was virtually identical on the GLP-1 and saline study days during both the basal (1.21 +/- 0.15 vs. 1.32 +/- 0.19 mol/l per 6 h) and prandial (0.56 +/- 0.14 vs. 0.56 +/- 0.10 mol/l per 6 h) insulin infusions. During both the basal and prandial insulin infusions, glucose disappearance promptly increased after initiation of the glucose infusion to rates that did not differ on the GLP-1 and saline study days. Suppression of endogenous glucose production also was comparable on the GLP-1 and saline study days during both the basal (-2.7 +/- 0.3 vs. -3.1 +/- 0.2 micromol/kg) and prandial (-3.1 +/- 0.4 vs. -3.0 +/- 0.6 pmol/kg) insulin infusions. We conclude that when insulin and glucagon concentrations are matched, GLP-1 has negligible effects on either insulin action or glucose effectiveness in people with type 2 diabetes. These data strongly support the concept that GLP-1 improves glycemic control in people with type 2 diabetes by increasing insulin secretion, by inhibiting glucagon secretion, and by delaying gastric emptying rather than by altering extrapancreatic glucose metabolism. [ABSTRACT FROM AUTHOR]

Insulin-induced stimulation of muscle glucose uptake (MGU) is impaired in people with type 2 diabetes. To determine whether insulin-induced stimulation of splanchnic glucose uptake (SGU) is also impaired, we simultaneously measured leg glucose uptake (LGU) and SGU in 14 nondiabetic subjects and 16 subjects with type 2 diabetes using a combined organ catheterization-tracer infusion technique. Glucose was clamped at approximately 9.3 mmol/l, while insulin concentrations were maintained at approximately 72 pmol/l (low) and approximately 150 pmol/l (high) for 3 h each. Endogenous hormone secretion was inhibited with somatostatin. Total body glucose disappearance was lower (P < 0.01) and glucose production higher (P < 0.01) during both insulin infusions in the diabetic compared with the nondiabetic subjects, indicating insulin resistance. Splanchnic glucose production was higher (P < 0.05) in the diabetic subjects during the low but not the high insulin infusion. SGU was slightly lower in the diabetic than in the nondiabetic subjects during the low insulin infusion and 50-60% lower (P < 0.05) during the high insulin infusion. LGU (P < 0.001), but not SGU, was inversely correlated with the degree of visceral adiposity. The contribution of the indirect pathway to hepatic glycogen synthesis did not differ in the diabetic and nondiabetic subjects. In contrast, both flux through the UDP-glucose pool (P < 0.05) and the contribution of the direct pathway to glycogen synthesis (P < 0.01) were lower in the diabetic than in the nondiabetic subjects, indicating decreased uptake and/or phosphorylation of extracellular glucose. On the other hand, glycogenolysis was equally suppressed in both groups. In summary, type 2 diabetes impairs the ability of insulin to stimulate both MGU and SGU. The defect appears to reside at a proximal (e.g., glucokinase) metabolic step and is not related to the degree of visceral adiposity. These data suggest that impaired hepatic glucose uptake as well as MGU contribute to hyperglycemia in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

We reviewed charts and lab data of patients admitted to emergency center of a large cancer hospital for acute decompensated hyperglycemic crisis between Jan 2001 and Dec 2004, and identified 22 such patients (14 F, 41% White, 41% African American, 18% Hispanic; 55% pre-existing known diabetes(DM)). Fourteen (63%) had diabetic ketoacidesis, plasma glucose = 679±72 (mean ± SEM) mg/dL; 12 with metastatic solid; 2 hematological malignancies. 8 had hyperosmolar hyperglycemic state (HHS) without ketosis; glucose = 797±111 mg/dL, osmolality = 349±12 mosm/Kg; all had metastatic solid malignancies. At presentation 68% had lethargy / weakness, 46% polyuria / polydipsia, 36% nausea / vomiting and 23% dyspnea. Precipitating factors recognized (in 86%) by the treating physicians included use of glucocorticoids (55%), infection (l8%), and "non compliance" (14%). In addition 55% were depressed. In 12 known DM peak plasma glucose prior to the crisis was 318±43mg/dL and HbA1c (n=4) 10.0±0.3%. Two were on insulin sensitizers; 7 on secretagogues; one each on NPH and glargine insulin, and none on bolus plus basal insulin. In those not known to be DM plasma glucose was tested 23±6 (3 to 45) d after starting diabetogenic drugs [10± (1 to 14) d in known DM]. Acute decompensation occurred 12±7 (0 to 25) and 4±3 (0 to 28) d later. 17/22 died in 14±4mo after the crisis (median survival: 12mo). 13/22 were admitted to hospital for some reason over the previous 36± 12mo. 12/22 (7 known DM) had glucose >300 mg/dL during previous 54±18 (4-227) d before the crisis. In disease burden study, hospital pharmacy and lab data over 3 mo in 2006 revealed glucose >306 mg/dL in 261 out of 2537 (10%) patient admissions to cancer center. Of these 88 (34%) remained untreated for DM during the admission. Untested, unrecognized, untreated, or inadequately treated DM predates acute decompensated hyperglycemic crisis in significant proportion of patients with cancer. Half die within 12 mo after the crisis. Also, sizeable proportions (10%) of admitted cancer patients have uncontrolled DM, either neglected or labeled as "hyperglycemia". Our data highlights the importance of recognizing and treating DM in cancer patients to possibly reduce patient morbidity in cancer patients. [ABSTRACT FROM AUTHOR]

To determine if, and if so, the mechanism(s) by which Pioglitazone and Metformin alter FFA induced insulin resistance, type 2 diabetic subjects were infused with either Intralipid/heparin (IL) in amounts sufficient to maintain FFA in the range observed in poorly controlled diabetes (∼0.5 mmol/l) or matching amounts of glycerol in random order prior to and following four months of treatment with either Pioglitazone (n=16) or Metformin (n=15). Glucose was clamped at ∼5.3 mmol/l; endogenous hormone secretion inhibited with somatostatin; and insulin concentrations raised to ∼190 pmol/l by a 0.6 mU/kg/min insulin infusion. Prior to treatment, FFA impaired substantially (p<0.01) insulin induced stimulation of glucose uptake but minimally altered suppression of endogenous glucose production (EGP). Pioglitazone and Metformin both increased net insulin action (glucose infusion rate required to maintain euglycemia) in the presence (p<0.001) of elevated FFA but only Pioglitazone did so in the absence (p<0.01) of elevated FFA. Pioglitazone increased (p<0.01) glucose uptake and improved suppression (p<0.05) of EGP during IL to rates observed during glycerol infusion prior to treatment. However despite treatment with Pioglitazone, FFA still (i.e. compared to the post-treatment glycerol infusion) impaired the ability of insulin to stimulate (p<0.0001) glucose uptake and suppress EGP (p<0.01). In contrast when compared to pretreatment, whereas Metformin also increased (p<0.05) glucose uptake during IL, it did not enhance suppression of EGP either in the presence or absence of elevated FFA. On the other hand, elevated FFA (i.e. compared to the post-treatment glycerol infusion) had no effect on glucose uptake following treatment with Metformin. Thus, both Pioglitazone and Metformin improve net insulin action in the presence of elevated FFA. However, Metformin but not Pioglitazone prevents the inhibitory effects of FFA on insulin induced stimulation of glucose uptake. In contrast, ,while not totally preventing the stimulatory effects of elevated FFA on hepatic glucose release, Pioglitazone but not Metformin enhances insulin induced suppression of EGP. [ABSTRACT FROM AUTHOR]