The metabolic response to ingestion of proline with and without glucose

Ingested protein results in an increase in circulating insulin and glucagon concentrations and no change, or a slight decrease, in circulating glucose. In subjects with type 2 diabetes, when protein is ingested with glucose, insulin is further increased and the glucose rise is less than when glucose is ingested alone. Presumably these effects are due to the amino acids present in the proteins. The effects of individual amino acids, ingested in physiologic amounts, with or without glucose, have not been determined. Therefore, we have begun a systematic study of the response to ingested amino acids. Eight young, non-obese, subjects (4 men, 4 women) ingested 1 mmol proline/kg lean body mass, 25 g glucose, 25 g glucose + 1 mmol proline/kg lean body mass or water only on 4 separate occasions at 8 am. Blood was obtained before and after ingestion of the test meal over the following 150 minutes. Proline ingestion resulted in a 13-fold increase in the plasma proline concentration. This was decreased by 50% when glucose was ingested with proline. Proline alone had little effect on glucose, insulin, or glucagon concentrations. However, ingestion of proline with glucose resulted in a 23% attenuation of the glucose area response and no change in insulin response compared with the response to that of glucose alone. A glucose-stimulated decrease in glucagon was further facilitated by proline. Ingested proline is readily absorbed. It reduces the glucose-induced increase in glucose concentration in the presence of an unchanged insulin and a decreased glucagon response.     

Effects of glucose, galactose, and lactose ingestion on the plasma glucose and insulin response in persons with non-insulin-dependent diabetes mellitus

Galactose usually is ingested as lactose, which is composed of equimolar amounts of glucose and galactose. The contribution of galactose to the increase in glucose and insulin levels following ingestion of equimolar amounts of galactose and glucose, or lactose, has not been reported in people with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, we studied the effects of galactose ingestion alone, as well as with glucose either independently or in the form of lactose, in subjects with untreated NIDDM. Eight male subjects with untreated NIDDM ingested 25 g glucose, 25 g galactose with or without 25 g glucose, or 50 g lactose as a breakfast meal in random sequence. They also received 50 g glucose on two occasions as a reference. Water only was given as a control meal. Plasma galactose, glucose, glucagon, α-amino nitrogen (AAN), nonesterified fatty acids (NEFA), and serum insulin and C-peptide concentrations were determined over a 5-hour period. The integrated area responses were quantified over the 5-hour period using the water control as a baseline. Following ingestion of 25 g galactose, the maximal increase in plasma galactose concentration was 1 mmol/L. The mean maximal increases in plasma galactose concentration following ingestion of 25 g galactose + 25 g glucose or following 50-g lactose meals were similar and were only 12% of that following ingestion of galactose alone (P < .05). The mean galactose area response over the water control for the 25-g galactose meal was 0.95 ± 0.31 mmol · h/L. That following ingestion of 25 g glucose + 25 g galactose or following the 50-g lactose meal was 0.17 ± 0.07 and 0.13 ± 0.05 mmol · h/L, respectively. Following ingestion of 25-g or 50-g glucose meals, the galactose area responses increased only slightly. The mean glucose area response following the 50-g glucose meals was 14.8 ± 2.5 mmol · h/L. Glucose area responses following ingestion of 25 g galactose, 25 g glucose, 25 g glucose + 25 g galactose, and 50 g lactose were 11%, 49%, 54%, and 60% of that observed following ingestion of 50 g glucose, respectively. The mean insulin area response following ingestion of the 50-g glucose meals was 965 ± 162 pmol · h/L. The insulin area responses observed with 25 g galactose, 25 g glucose, 25 g glucose + 25 g galactose, and 50 g lactose were 24%, 51%, 81%, and 85% of that observed with the 50-g glucose meals, respectively. The C-peptide data confirmed the insulin data. The glucagon concentration was unchanged after galactose ingestion and decreased after glucose ingestion. However, the decrease in the glucagon area response observed with 25 g galactose + 25 g glucose or 50 g lactose was less than that with ingestion of 25 g glucose alone. The latter suggests inhibition of the glucagon response to glucose by the added galactose. In conclusion, ingested galactose results in only a modest increase in plasma glucose concentration. The glucose area responses to galactose and glucose are additive. Oral galactose is a relatively potent insulin secretagogue, and the insulin response is also additive to that following glucose ingestion. Ingestion of glucose with galactose markedly reduces the increase in plasma galactose concentration. The mechanism of this effect remains to be defined.     

Metabolic response to cottage cheese or egg white protein, with or without glucose, in type II diabetic subjects.

Test meals with 25 g protein in the form of cottage cheese or egg white were given with or without 50 g glucose to male subjects with mild to moderately severe, untreated, type II diabetes. Water was given as a control meal. The glucose, insulin, C-peptide, alpha amino nitrogen (AAN), glucagon, plasma urea nitrogen (PUN), nonesterified fatty acid (NEFA), and triglyceride area responses were determined using the water meal as a baseline. The glucose area responses following ingestion of cottage cheese or egg white were very small compared with those of the glucose meal, and were not significantly different from one another. The serum insulin area response was 3.6-fold greater following ingestion of cottage cheese compared with egg white (309 v 86 pmol/L.h). The simultaneous ingestion of glucose with cottage cheese or egg white protein decreased the glucose area response to glucose by 11% and 20%, respectively. When either protein was ingested with glucose, the insulin area response was greater than the sum of the individual responses, indicating a synergistic effect (glucose alone, 732 pmol/L.h; glucose with cottage cheese, 1,637 pmol/L.h; glucose with egg white, 1,213 pmol/L.h). The C-peptide area response was similar to the insulin area response. The AAN area response was approximately twofold greater following ingestion of cottage cheese compared with egg white. Following ingestion of glucose, it was negative. When protein was ingested with glucose, the AAN area responses were additive. The glucagon area response was similar following ingestion of cottage cheese or egg white protein. Following glucose ingestion, the glucagon area response was negative.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral glucose appearance rate following fructose ingestion in normal subjects

Ingested fructose is rapidly utilized by the liver and is either stored as glycogen, converted to glucose, or oxidized to CO2 for energy. The glycemic response to fructose is known to be modest. However, the relative importance of these pathways in humans is unclear. In the present study, a tritiated glucose tracer dilution technique was used to determine the effect of fructose ingestion on the glucose appearance rate (Ra) in the peripheral circulation over an 8-hour period beginning at 8:00 AM. Six normal healthy males ingested 50 g fructose with 500 mL water. On a separate occasion, the same subjects received 500 mL water without fructose as a control. Serum insulin, triglycerides, plasma glucagon, glucose, lactate, alanine, urea nitrogen, and total amino acids also were determined. The plasma glucose concentration was not significantly different following ingestion of fructose or water, other than a transient increase beginning at 8:30 AM of 0.8 mmol/L in response to ingested fructose. Glucose appearing in the peripheral circulation as a result of ingestion of 50 g fructose was calculated to be 9.8 +/- 2.4 g. Following the ingestion of fructose, there was a small increase in glucagon but a 2-fold increase in insulin concentration. There was a large transient increase in lactate and alanine concentrations. The total amino acid concentration remained unchanged, as did the urea production rate. In summary, in men fasted overnight, ingestion of 50 g fructose resulted in a modest increase in the circulating glucose concentration. However, it is likely that a larger proportion of the ingested fructose was converted to glucose in the liver and stored as glycogen and that fructose substituted, at least in part, for lactate and alanine as a gluconeogenic substrate. The increase in glucose production occurred even in the presence of an increase in the insulin concentration and an unchanged glucagon concentration. The metabolic fate of the remaining fructose is yet to be determined.     

The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects

We previously have shown that ingested beef protein is just as potent as glucose in stimulating a rise in insulin concentration in type II diabetic patients. A synergistic effect was seen when given with glucose. Therefore, we considered it important to determine if other common dietary proteins also strongly stimulate an increase in insulin concentration when given with glucose. Seventeen type II (non-insulin-dependent) untreated diabetic subjects were given single breakfast meals consisting of 50 g glucose, or 50 g glucose plus 25 g protein in the form of lean beef, turkey, gelatin, egg white, cottage cheese, fish, or soy. The peripheral plasma concentrations of glucose, insulin, glucagon, alpha amino nitrogen, urea nitrogen, free fatty acids, and triglycerides were measured. Following ingestion of the meals containing protein, the plasma insulin concentration was increased further and remained elevated longer compared with the meal containing glucose alone. The relative area under the insulin response curve was greatest following ingestion of the meal containing cottage cheese (360%) and was least with egg white (190%) compared with that following glucose alone (100%). The glucose response was diminished following ingestion of the meals containing protein with the exception of the egg white meals. The peripheral glucagon concentration was decreased following ingestion of glucose alone and increased following all the meals containing protein. The alpha amino nitrogen concentration varied considerably. It was decreased after glucose alone, was unchanged after egg white ingestion, and was greatest after ingestion of gelatin. The free fatty acid concentration decrease was 4- to 8-fold greater after the ingestion of protein with glucose compared with ingestion of glucose alone.     

Impact of glucagon response on postprandial hyperglycemia in men with impaired glucose tolerance and type 2 diabetes mellitus

Glucagon is the physiological antagonist of insulin. Postprandial (pp) hyperglycemia in impaired glucose tolerance (IGT) and in type 2 diabetes mellitus (T2DM) may also depend on irregularities in glucagon secretion. This study investigated the glucagon excursion after a lipid-glucose-protein tolerance test in subjects with different stages of glucose intolerance. We also analyzed the relationship between pp glucagon secretion and hyperglycemias. A total of 64 men (27 healthy subjects with normal glucose tolerance [NGT], 15 with IGT, and 22 with T2DM) were examined. Plasma glucose (PG), insulin, proinsulin, free fatty acids, and triglycerides were measured in the fasting state and at 30 minutes and 2, 3, 4, and 6 hours after the intake of the test meal, which contained 126 g carbohydrates, 92 g fat, and 17 g protein. Postprandial concentrations of metabolic parameters were calculated as area under the curve (AUC). Glucagon was measured in the fasting state and at 30 minutes and 2 and 4 hours pp. Early glucagon increment was defined as glucagon at 30 minutes minus fasting glucagon. The insulin response was quantified as insulin increment divided by PG increment in the corresponding time. Insulin resistance was calculated using lomeostasis model assessment (HOMA). Fasting glucagon was significantly increased in IGT vs NGT (P<.05), and early glucagon increment was significantly higher in T2DM vs NGT and IGT (P<.05). The 2-hour glucagon concentration after the load (AUC) was increased in IGT and T2DM vs NGT (P<.05). Early glucagon increment and the 2-hour AUC of glucagon were strongly correlated to pp glycemia (r=0.494 and P=.001, and r=0.439 and P=.003, respectively). An inverse correlation was observed between early glucagon increment and insulin response at 30 minutes and 2 hours after the meal load (r=-0.287 and P=.026, and r=-0.435 and P=.001, respectively). The 2-hour AUC of glucagon was significantly associated with insulin resistance (r=0.354, P=.020). Multivariate analysis revealed 2-hour insulin response and early glucagon increment as significant independent determinants of the AUC of PG in IGT (R=0.787). In T2DM, 2-hour insulin response, insulin resistance, and early glucagon increment were significant determinants of the AUC of PG (R=0.867). Our study suggests an important role for the irregularities in glucagon response in the pp glucose excursion after a standardized oral mixed meal in IGT and in T2DM. According to our data, a bihormonal imbalance starts before diabetes is diagnosed. Prospective studies are needed to evaluate the impact of glucagon on the progression of glucose intolerance and the possible effects of medicinal suppression of glucagon increment to prevent the progression of glucose tolerance.     

Failure of carbohydrate to spare leucine oxidation in obese subjects

Leucine kinetics were studied in six obese subjects (W/H2 = 39 +/- 4) and six normal subjects (W/H2 = 21 +/- 3) before and after an oral load of 150 g glucose. An intravenous infusion of 1(-13)C leucine was given to the fasting subjects for 450 min: a steady state of plasma leucine enrichment was established 90 min after the start of the infusion, and the glucose load was given 220 min after the start of the infusion. Compared with the lean controls the obese subjects showed a greater area under the curve of blood glucose after the glucose load (P less than 0.025) and higher insulin and glucagon levels both before and after the meal (P less than 0.05), thus indicating the well-known insulin insensitivity of obese (but not diabetic) subjects with respect to glucose metabolism. After the glucose load the lean subjects showed a significant and sustained decrease in leucine oxidation (from 20.0 +/- 2.2 to 13.3 +/- 1.5 mumol/kg LBM/h: P less than 0.01). This response is similar to that observed when insulin-dependent diabetic subjects are given insulin. However the obese subjects showed no decrease in leucine oxidation after the glucose meal (20.3 +/- 1.9 before, and 21.2 +/- 3.6 after). This indicates that obese subjects show insensitivity to the action of insulin with respect to protein metabolism as well as carbohydrate metabolism.     

Effects of meal size and composition on incretin, α-cell, and β-cell responses

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the β-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insulin, glucagon, and incretin responses. In a randomized crossover study, 18 subjects with type 2 diabetes mellitus and 6 healthy volunteers underwent three 4-hour meal tolerance tests (small carbohydrate [CH]-rich meal, large CH-rich meal, and fat-rich meal). Non-model-based and model-based estimates of β-cell function and incremental areas under the curve of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP were calculated. Mixed models and Friedman tests were used to test for differences in meal responses. The large CH-rich meal and fat-rich meal resulted in a slightly larger insulin response as compared with the small CH-rich meal and led to a slightly shorter period of hyperglycemia, but only in healthy subjects. Model-based insulin secretion estimates did not show pronounced differences between meals. Both in healthy individuals and in those with diabetes, more CH resulted in higher GLP-1 release. In contrast with the other meals, GIP release was still rising 2 hours after the fat-rich meal. The initial glucagon response was stimulated by the large CH-rich meal, whereas the fat-rich meal induced a late glucagon response. Fat preferentially stimulates GIP secretion, whereas CH stimulates GLP-1 secretion. Differences in meal size and composition led to differences in insulin and incretin responses but not to differences in postprandial glucose levels of the well-controlled patients with diabetes.     

The alpha cell response to glucose change during perfusion of anti-insulin serum in pancreas isolated from normal rats

Summary To determine the effect of neutralization of endogenous insulin upon the glucagon response to a rise and fall of glucose concentration, pancreata isolated from normal rats were perfused with either a potent anti-pork insulin guinea pig serum or a nonimmune guinea pig serum for 30 min. During this period glucose concentration was changed from 100 mg/dl to either 130, 180 or 80 mg/dl for 10 min. Antiserum perfusion at 100 mg/dl caused an approximately two-fold increase in glucagon which was not suppressed by an increase in glucose concentration to either 130 or 180 mg/dl, although glucagon secretion was significantly suppressed in the control experiments in which nonimmune serum was perfused. However, the 0.38±0.21 ng/min rise in glucagon secretion in response to a reduction in glucose concentration to 80 mg/dl in the control experiments was not abolished by antiserum perfusion but, instead, was enhanced (2.66±0.60 ng/min). These findings suggest that insulin may be required for glucose-mediated suppression of glucagon in the isolated pancreas of normal rats but not for stimulation of glucagon secretion by mild glucopenia. Alternatively, neutralization of insulin-mediated release-inhibition of glucagon secretion may simply have altered alpha cell responsiveness in a direction that desensitized it nonspecifically to suppression and sensitized it to stimulation.Senior Medical Investigator, Dallas Veterans Administration     

Contribution of skeletal muscle mass on sex differences in 2-hour plasma glucose levels after oral glucose load in Thai subjects with normal glucose tolerance

Women have higher 2-hour plasma glucose levels after oral glucose challenge than men. The smaller skeletal muscle mass in women may contribute to the higher postload glucose levels. The objective of this study was to test the hypothesis that the different amount of skeletal muscle mass between men and women contributed to sex difference in postload plasma glucose levels in subjects with normal glucose tolerance. Forty-seven Thai subjects with normal glucose tolerance, 23 women and 24 age- and body mass index-matched men, were studied. Body fat, abdominal fat, and appendages lean mass were measured by dual-energy x-ray absorptiometry. Skeletal muscle insulin sensitivity was determined by euglycemic-hyperinsulinemic clamp. First-phase insulin secretion and hepatic insulin sensitivity were determined from oral glucose tolerance data. β-Cell function was estimated from the homeostasis model assessment of %B by the homeostasis model assessment 2 model. Correlation and linear regression analysis were performed to identify factors contributing to variances of postload 2-hour plasma glucose levels. This study showed that women had significantly higher 2-hour plasma glucose levels and smaller skeletal muscle mass than men. Measures of insulin secretion and insulin sensitivity were not different between men and women. Male sex (r = −0.360, P = .013) and appendages lean mass (r = −0.411, P = .004) were negatively correlated with 2-hour plasma glucose, whereas log 2-hour insulin (r = 0.571, P < .0001), total body fat (r = 0.348, P = .016), and log abdominal fat (r = 0.298, P = .042) were positively correlated with 2-hour plasma glucose. The correlation of 2-hour plasma glucose and sex disappeared after adjustment for appendages lean mass. By multivariate linear regression analysis, log 2-hour insulin (β = 18.9, P < .0001), log 30-minute insulin (β = −36.3, P = .001), appendages lean mass (β = −1.0 × 10⁻³, P = .018), and hepatic insulin sensitivity index (β = −17.3, P = .041) explained 54.2% of the variance of 2-hour plasma glucose. In conclusion, the higher postload 2-hour plasma glucose levels in women was not sex specific but was in part a result of the smaller skeletal muscle mass. The early insulin secretion, hepatic insulin sensitivity, and skeletal muscle mass were the significant factors negatively predicting 2-hour postload plasma glucose levels in Thai subjects with normal glucose tolerance.     

Carbohydrate metabolism in pregnancy. XIV. Relationships between circulating glucagon,insulin, glucose and amino acids in response to a “mixed meal” in late pregnancy

Gestational influences upon the changes in circulating glucose, amino acids, insulin, and glucagon after the ingestion of a “mixed meal” containing carbohydrate (50 g), protein (25 g), and fat (10 g) were examined. Nine subjects were tested during weeks 30–40 of gestation and again 6–8 wk postpartum. The “mixed meal” elicited greater and more prolonged increases in plasma glucose antepartum, whereas the increments in total serum amino acids were blunted at all time points. In the face of greater glycemic but lesser aminogenic stimulation, the integrated increase in plasma insulin was 60% greater antepartum than post partum, whereas the increment in glucagon was not significantly altered. Thus, integrated insulin/glucagon response was increased during antepartum studies. The insulin preponderance following alimentary challenge with mixed nutrients would suggest that the anabolism of ingested amino acids is “facilitated” during late human pregnancy.     

Minor physiological relevance of oral glucose tolerance test

The physiological relevance of the oral glucose tolerance test was evaluated in ten healthy nonobese subjects and nine subjects with slightly impaired glucose tolerance. In random order, all subjects received a 50 g oral glucose tolerance test or a standardized breakfast meal of equivalent carbohydrate content. Changes in plasma glucose, insulin, and pancreatic glucagon concentrations were measured. In both groups, plasma glucose increased significantly during the oral glucose tolerance test and the meal test but the incremental glucose area (0-60 min) of the oral glucose tolerance test was about 350% and 120% greater than that of the mean test (p less than 0.001) in the normals and the patients with impaired glucose tolerance, respectively. In both groups, insulin responded almost similarly to the oral glucose tolerance test and the meal test whereas plasma glucagon declined significantly during the oral glucose tolerance test only (p less than 0.001). Glucagon remained unchanged during the meal test in the normals and increased slightly (p less than 0.05) in the group with impaired glucose tolerance. These data show that the response of glucose, insulin and glucagon to an oral glucose tolerance test in various respects is different to that obtained by the more physiological stimulation with a breakfast meal.     

The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes

Mealtime amylin replacement with the human amylin analog pramlintide as an adjunct to insulin therapy improves postprandial glycemia and long-term glycemic control in type 1 diabetes. Preclinical animal studies indicate that these complementary effects may result from at least 2 independent mechanisms: a slowing of nutrient delivery to the small intestine and a suppression of nutrient-stimulated glucagon secretion. The former effect of pramlintide has previously been demonstrated in patients with type 1 diabetes. The present studies characterize the effect of pramlintide on postprandial glucagon secretion in this patient population. Plasma glucagon and glucose concentrations were measured before and after a standardized liquid meal in 2 separate randomized, double-blind, placebo-controlled studies of pramlintide administration to patients with type 1 diabetes. In a 2-day crossover study, 18 patients received a 5-hour intravenous infusion of pramlintide (25 microg/h or 50 microg/h) or placebo in addition to subcutaneous (SC) insulin injections. In a 14-day parallel-group study, 84 patients received SC injections of 30, 100, or 300 microg of pramlintide or placebo 3 times daily in addition to SC injections of insulin. In both studies plasma glucagon concentrations increased in response to the meal in the placebo-plus-insulin group but not in any of the pramlintide-treated groups (all pramlintide treatment arms v placebo, P <.05). We conclude that mealtime amylin replacement with pramlintide prevents the abnormal meal-related rise in glucagonemia in insulin-treated patients with type 1 diabetes, an effect that likely contributes to its ability to improve postprandial glucose homeostasis and long-term glycemic control.     

Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas

The effects of increasing concentrations of leucine (0.2, 2.0, and 15.0 mmol/liter) on glucagon secretion from the perfused rat pancreas were examined at various glucose levels (0, 3.3, or 8.3 mmol/liter) and in the absence or presence of either arginine (5.0 mmol/liter) or glutamine (10.0 mmol/liter). At a low glucose concentration (3.3 mmol/liter), leucine caused a dose-related biphasic increase in glucagon output in the absence of arginine, but only a transient increase in the presence of the latter amino acid. These positive responses were markedly reduced and, on occasion, abolished at a high glucose concentration (8.3 mmol/liter). Moreover, at a low glucose concentration (3.3 mmol/liter) and in the presence of arginine, the highest concentration of leucine (15.0 mmol/liter) provoked a sustained and reversible inhibition of glucagon release. Likewise, leucine (15.0 mmol/liter) reversibly inhibited glucagon secretion evoked by glutamine in the absence of glucose. Thus, leucine exerted a dual effect on the secretion of glucagon, the inhibitory effect of leucine prevailing at a high concentration of the branched chain amino acid and when glucagon secretion was already stimulated by arginine or glutamine. At a physiological concentration (0.2 mmol/liter), however, leucine was a positive stimulus for glucagon release, especially in the absence of another amino acid. Concomitantly, leucine was always a positive stimulus for both insulin and somatostatin secretion. The intimate mechanisms involved in the dual effect of leucine on glucagon secretion remain to be elucidated.     

Pathogenetic aspects of the obese-hyperglycemic syndrome in mice (genotypeobob): I. Function of the pancreatic B-cells

Summary The insulin secretion has been studied in both fed and starved obese-hyperglycemic mice (genotypeobob) and their lean siblings. Groups of mice, 2–15 months old, were injected intravenously with either glucose or glucagon, and the serum levels of glucose and immunoreactive insulin measured. Injection of glucose, 3.75 g per kg body weight, caused a prompt increase of the serum insulin in allobob mice except for the group of 4 months old animals with free access to food. In contrast to the lean siblings the obese mice displayed an enhanced disappearance rate of glucose from serum with increasing age. Administration of glucagon effected a marked and prompt increase of the serum insulin concentration in all animals. Hence the delayed and low insulin response previoulsy observed in human diabetics was not found in mice with the obese-hyperglycemic syndrome.This work was supported by grants from the Swedish Medical Research Council (B69-12X-109), Swedish Diabetes Association, Nordic Insulin Foundation and the United States Public Health Service (AM-12535).     

Effects of gastric bypass surgery on glucose absorption and metabolism during a mixed meal in glucose-tolerant individuals

Aims/hypothesis

Roux-en-Y gastric bypass surgery (RYGB) improves glucose tolerance in patients with type 2 diabetes, but also changes the glucose profile in response to a meal in glucose-tolerant individuals. We hypothesised that the driving force for the changed postprandial glucose profiles after RYGB is rapid entry of glucose into the systemic circulation due to modified gastrointestinal anatomy, causing hypersecretion of insulin and other hormones influencing glucose disappearance and endogenous glucose production.

Methods

We determined glucose absorption and metabolism and the rate of lipolysis before and 3 months after RYGB in obese glucose-tolerant individuals using the double-tracer technique during a mixed meal.

Results

After RYGB, the postprandial plasma glucose profile changed, with a higher peak glucose concentration followed by a faster return to lower than basal levels. These changes were brought about by changes in glucose kinetics: (1) a more rapid appearance of ingested glucose in the systemic circulation, and a concomitant increase in insulin and glucagon-like peptide-1 secretion; (2) postprandial glucose disappearance was maintained at a high rate for a longer time after RYGB. Endogenous glucose production was similar before and after surgery. Postoperative glucagon secretion increased and showed a biphasic response after RYGB. Adipose tissue basal rate of lipolysis was higher after RYGB.

Conclusions/interpretation

A rapid rate of absorption of ingested glucose into the systemic circulation, followed by increased insulin secretion and glucose disappearance appears to drive the changes in the glucose profile observed after RYGB, while endogenous glucose production remains unchanged.

Trial registration

ClinicalTrials.gov NCT01559792.

Funding

The study was part of the UNIK program: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk). Funding was received from the Novo Nordisk foundation and the Strategic Research Counsel for the Capital Area and Danish Research Agency. The primary investigator received a PhD scholarship from the University of Copenhagen, which was one-third funded by Novo Nordisk.     

Metasomatotrophic diabetes and its induction: Basal insulin secretion and insulin release responses to glucose,glucagon, arginine and meals

Summary Growth hormone treatment produced somatotrophic diabetes, with hyperglycaemia, polyuria, glycosuria and elevation in serum non-esterified fatty acids (NEFA) in dogs. Early in this diabetes, fasting serum immunoreactive insulin (IRI) rose 20-fold, the insulin/glucose (I/G) ratio rose 10-fold and in response to glucose infusion, the rise in IRI was twice the normal. In the latter half of the continued growth hormone treatment, the intensity of the diabetes increased, serum IRI declined to the normal level and the I/G ratio became subnormal. Late in the treatment, following glucose infusion, there was no change in serum IRI, no fall in NEFA and further depression of glucose tolerance. In metasomatotrophic diabetes, in which hyperglycaemia, glycosuria and high NEFA level persisted, fasting serum IRI was normal during several months, then became subnormal and the I/G ratio was diminished further. Following glucose IV there was no change in serum IRI, no fall in NEFA and low glucose tolerance. The normally-occurring rises in serum IRI following arginine and glucagon IV and after the ingestion of a meal were absent. These permanently diabetic dogs were responsive to insulin IV. The insulin content of the pancreas was reduced to about 1.2% of the normal after 14 months of this diabetes. From the sequence of change it is concluded that growth hormone induced metasomatotrophic diabetes by causing excessive secretion of insulin under basal and stimulative conditions, leading to permanent loss of function of the beta cells of the pancreatic islets, to such an extent that basal insulin secretion was low and the ability to secrete extra insulin in response to stimuli was lost.     

Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse.

We examined the effects of a single intravenous injection of homologous islet amyloid polypeptide (IAPP) on the plasma levels of glucagon, insulin and glucose in the freely fed mouse. It was observed that IAPP suppressed basal glucagon levels concomitant with a decrease of the blood glucose concentrations. Basal plasma insulin levels were not affected. IAPP did not appreciably modulate the plasma concentration of glucose, insulin or glucagon after an intravenous glucose load. Further, IAPP inhibited the insulin secretory response to beta 2-adrenoceptor stimulation. IAPP also lowered the plasma glucagon levels following beta 2-adrenoceptor stimulation, whereas no apparent effect on plasma levels of glucose was observed. The data suggest that IAPP suppresses glucagon secretion and lowers blood glucose levels in the freely fed mouse. It might also exhibit a negative feedback inhibition on beta 2-adrenoceptor-induced insulin secretion, but has little influence on glucose-induced insulin release. Since IAPP is co-secreted with insulin, it is not inconceivable, that in the freely fed mouse, IAPP may act to amplify the blood glucose lowering effect of insulin through a direct suppression of glucagon secretion via the islet microcirculation.     

Plasma glucagon suppressibility after oral glucose in obese subjects with normal and impaired glucose tolerance

Blood glucose, plasma insulin, and glucagon responses after a 75 g oral glucose-tolerance test were assessed in 9 normal controls, 5 obese nondiabetics (ON), 5 obese nondiabetics with fasting hyperinsulinemia (obese “resistant” nondiabetics—OR), 9 obese with impaired glucose tolerance (O-IGT), and 9 nonobese insulin-dependent diabetics (IDD). Fasting plasma glucagon concentrations were significantly higher in all groups of patients in comparison to the normal controls. Insulin secretion, evaluated in all but the IDD, was similar to normal in the ON and increased in the OR and O-IGT. Normal glucagon suppression was observed in the lean controls and ON but not in OR, O-IGT, and IDD. We suggested that the resistance to glucagon suppression after glucose load in the OR and O-IGT in the presence of increased insulin response could be an indication that the A cell participates in the relative insulin insensitivity of these subjects.     

Effects of leucine on insulin secretion and beta cell membrane potential in mouse islets of Langerhans

Leucine is known to enhance insulin secretion from islets of Langerhans, and insulin promotes leucine uptake in peripheral tissues. The present studies were designed to elucidate the effects of leucine on glucose responsiveness and stimulus secretion coupling in mouse islets of Langerhans. The effects of 20 mM leucine on insulin secretion and membrane potential were studied over a range of glucose concentrations (0-27.7 mM). Microdissected, perifused pancreatic islets from normal adult mice were used for both studies of insulin secretion and electrophysiology in order to make a close comparison between these measurements. Leucine enhanced the insulin secretion in the presence of 5.6, 11.1, and 22.2 mM glucose. In the presence of leucine, 27 mM glucose inhibited insulin secretion. In the absence of glucose-leucine did not induce electrical activity of the beta cell membrane, whereas in the presence of 5.6, 11.1, and 22.2 mM glucose leucine increased spike frequency. Thus, leucine shifts both the glucose-dependent insulin secretion and electrical activity toward lower glucose concentrations. It is concluded that leucine and glucose share a common metabolic pathway (citric acid cycle) for stimulatory effects. Leucine is deaminated to form 2-ketoisocaproic acid (KIC) and produce NH4+. We propose that in the absence of glucose this increases cytosolic pH, which in turn increases K+ permeability, and inhibits electrical activity and insulin secretion.