Mechanisms for abnormal postprandial glucose metabolism in type 2 diabetes.

To assess mechanisms for postprandial hyperglycemia, we used a triple-isotope technique ([\3-(3)H]glucose and [(14)C]bicarbonate and oral [6,6-dideutero]glucose iv) and indirect calorimetry to compare components of glucose release and pathways for glucose disposal in 26 subjects with type 2 diabetes and 15 age-, weight-, and sex-matched normal volunteers after a standard meal. The results were as follows: 1) diabetic subjects had greater postprandial glucose release (P<0.001) because of both increased endogenous and meal-glucose release; 2) the greater endogenous glucose release (P<0.001) was due to increased gluconeogenesis (P<0.001) and glycogenolysis (P=0.01); 3) overall tissue glucose uptake, glycolysis, and storage were comparable in both groups (P>0.3); 4) glucose clearance (P<0.001) and oxidation (P=0.004) were reduced, whereas nonoxidative glycolysis was increased (P=0.04); and 5) net splanchnic glucose storage was reduced by approximately 45% (P=0.008) because of increased glycogen cycling (P=0.03). Thus in type 2 diabetes, postprandial hyperglycemia is primarily due to increased glucose release; hyperglycemia overcomes the effects of impaired insulin secretion and sensitivity on glucose transport, but intracellular defects persist so that pathways of glucose metabolism are abnormal and glucose is shunted away from normal sites of storage (e.g., liver and muscle) into other tissues.

Effects of glimepiride and glyburide on glucose counterregulation and recovery from hypoglycemia.

Severe hypoglycemia, the most serious side effect of sulfonylurea therapy, has been reported to occur more frequently with glyburide than glimepiride. The present studies were undertaken to test the hypothesis that a differential effect on glucagon secretion may be involved. We performed hyperinsulinemic hypoglycemic (approximately 2.5 mmol/L) clamps in 16 healthy volunteers who received in randomized order placebo, glyburide (10 mg), and glimepiride (4 mg) just before beginning the insulin infusion and measured plasma glucagon, insulin, C-peptide, glucagon, epinephrine, cortisol, and growth hormone levels during the clamp and during a 3-hour recovery period after discontinuation of the insulin infusion. Neither sulfonylurea altered glucagon responses or those of other counterregulatory hormones (except cortisol) during the clamp. However, glyburide delayed plasma glucose recovery from hypoglycemia (plasma glucose at end of recovery period: control, 4.9 +/- 0.2 mmol/L; glyburide, 3.7 +/- 0.2 mmol/L; P = .0001; glimepiride, 4.5 +/- 0.2 mmol/L; P = .08). Despite lower plasma glucose levels, glyburide stimulated insulin secretion during this period (0.89 +/- 0.13 vs 1.47 +/- 0.15 pmol x kg(-1) x min(-1), control vs glyburide; P = .001), whereas glimepiride did not (P = .08). Short-term administration of glyburide or glimepiride did not alter glucagon responses during hypoglycemia. In contrast, during recovery from hypoglycemia, glyburide but not glimepiride inappropriately stimulates insulin secretion at low plasma glucose levels. This differential effect on insulin secretion may be an important factor in explaining why glyburide causes severe hypoglycemia more frequently than glimepiride.

Increasing the decrement in insulin secretion improves glucagon responses to hypoglycemia in advanced type 2 diabetes.

OBJECTIVE: In advanced beta-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion. RESEARCH DESIGN AND METHODS: Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced beta-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (approximately 2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control. RESULTS: Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion approximately 1.9-fold (P < 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P = 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 +/- 0.20 vs. 0.81 +/- 0.17 pmol x kg(-1) x min(-1), P < 0.001). This was associated with more than twofold-greater glucagon responses (42 +/- 11 vs. 19 +/- 8 ng/l, P < 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 +/- 50 vs. 453 +/- 50 ng/l, P = 0.78). CONCLUSIONS: Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced beta-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced beta-cell failure may at least partially be due to a reduced decrement in insulin secretion.

Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans.

OBJECTIVE: Animal and in vitro studies indicate that a decrease in beta-cell insulin secretion, and thus a decrease in tonic alpha-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear. RESEARCH DESIGN AND METHODS: We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from -60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin. RESULTS: During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose ( approximately 2.6 mmol/l) and insulin levels ( approximately 570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol . kg(-1) . min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 0.12 pmol . kg(-1) . min(-1) at baseline to 0.25 +/- 0.09 pmol . kg(-1) . min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol . kg(-1) . min(-1), P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with approximately 30% lower plasma glucagon concentrations (109 +/- 7 vs. 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were approximately 70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion. CONCLUSIONS: These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.

Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma glucose and hemoglobin a1c values.

BACKGROUND: Increased fasting plasma glucose (FPG) and 2-hour postchallenge plasma glucose (PCPG) levels with normal hemoglobin A1c (HbA1c) levels are recognized as risk factors for cardiovascular disease. We undertook this study to determine the relationships between FPG and 2-hour PCPG levels over the normal HbA1c range and to assess the need to control FPG and 2-hour PCPG levels to achieve HbA1c targets recommended by the American Diabetes Association (ADA), International Diabetes Federation (IDF), and American College of Endocrinology (ACE). METHODS: The data of all healthy individuals with HbA1c values less than 7.0% (N = 457) who underwent oral glucose tolerance tests between 1986 and 2002 for either screening as potential research volunteers (93%) or diagnostic purposes (7%) were analyzed. RESULTS: Of 404 individuals with normal HbA1c levels (<6.0%), 60% had normal glucose tolerance, 33% had impaired glucose tolerance, 1% had isolated impaired FPG, and 6% had type 2 diabetes mellitus. Of 161 individuals without normal glucose tolerance, 80% had normal FPG levels. Both FPG and 2-hour PCPG levels increased as HbA1c increased and were significantly correlated (r = 0.63, P<.001), but the 2-hour PCPG level increased at a rate 4 times greater than FPG and accounted for a greater proportion of HbA1c. People who met the IDF and ACE HbA1c targets (<6.5%) had significantly lower 2-hour PCPG levels than those who met the ADA target (<7.0%) (P =.03), whereas FPG levels were similar. CONCLUSIONS: Most individuals with HbA1c values between 6.0% and 7.0% have normal FPG levels but abnormal 2-hour PCPG levels, suggesting that an upper limit of normal for FPG at 110 mg/dL (6.11 mmol/L) is too high and that attempts to lower HbA1c in these individuals will require treatment preferentially directed at lowering postprandial glucose levels.

Pathways for glucose disposal after meal ingestion in humans.

To characterize postprandial glucose disposal more completely, we used the tritiated water technique, a triple-isotope approach (intravenous [3-H(3)]glucose and [(14)C]bicarbonate and oral [6,6-(2)H(2)]glucose) and indirect calorimetry to assess splanchnic and peripheral glucose disposal, direct and indirect glucose storage, oxidative and nonoxidative glycolysis, and the glucose entering plasma via gluconeogenesis after ingestion of a meal in 11 normal volunteers. During a 6-h postprandial period, a total of approximately 98 g of glucose were disposed of. This was more than the glucose contained in the meal ( approximately 78 g) due to persistent endogenous glucose release ( approximately 21 g): splanchnic tissues initially took up approximately 23 g, and an additional approximately 75 g were removed from the systemic circulation. Direct glucose storage accounted for approximately 32 g and glycolysis for approximately 66 g (oxidative approximately 43 g and nonoxidative approximately 23 g). About 11 g of glucose appeared in plasma as a result of gluconeogenesis. If these carbons were wholly from glucose undergoing glycolysis, only approximately 12 g would be available for indirect pathway glycogen formation. Our results thus indicate that glycolysis is the main initial postprandial fate of glucose, accounting for approximately 66% of overall disposal; oxidation and storage each account for approximately 45%. The majority of glycogen is formed via the direct pathway ( approximately 73%).