Insulin Excursions Research Articles

Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes.

We have demonstrated high heritability of insulin secretion measured as acute insulin response to glucose times insulin sensitivity (disposition index). Furthermore, we showed that obese normoglycemic family members of a type 2 diabetic proband failed to compensate for the insulin resistance of obesity by increasing insulin secretion. In this study, we tested the primary hypotheses that previously described variants in the pancreatic sulfonylurea receptor gene (SUR1 or ABCC8), glucokinase (GCK) gene, or hepatocyte nuclear factor 1alpha (TCF1 or HNF1alpha) gene contribute to the inherited deficiencies of insulin secretion and beta-cell compensation to insulin resistance, as well as the secondary hypotheses that these variants altered insulin sensitivity. We typed 124 nondiabetic members of 26 familial type 2 diabetic kindreds who had undergone tolbutamide-modified intravenous glucose tolerance tests for two variants of the ABCC8 (sulfonylurea) gene, two variants of the GCK gene, and one common amino acid variant in the TCF1 (HNF1alpha) gene. All family members were classified as normal or having impaired glucose tolerance based on oral glucose tolerance testing. We used minimal model analysis to calculate the insulin sensitivity index (S1) and glucose effectiveness (SG), and acute insulin response to glucose was calculated as the mean insulin excursion above baseline during the first 10 min after the glucose bolus. Disposition index (DI), a measure of beta-cell compensation for insulin sensitivity, was calculated as insulin sensitivity times acute insulin response. Effects of polymorphisms were determined using mixed effects models that incorporated family membership and by a likelihood analysis that accounted for family structure through polygenic inheritance. An intronic variant of the ABCC8 gene just upstream of exon 16 was a significant determinant of both DI and an analogous index based on acute insulin response to tolbutamide. Surprisingly, heterozygous individuals showed the lowest indexes, whereas the DI in the two homozygous states did not differ significantly. Neither the exon 18 variant nor the variants in the GCK and TCF1 genes were significant in this model. However, combined genotypes of ABCC8 exon 16 and 18 variants again significantly predicted both indexes of glucose and tolbutamide-stimulated insulin secretion. Unexpectedly, a variant in the 3' untranslated region of the GCK gene interacted significantly with BMI to predict insulin sensitivity. The exon 16 variant of the ABCC8 gene reduced beta-cell compensation to the decreased insulin sensitivity in the heterozygous state. This may explain the observation from several groups of an association of the ABCC8 variants in diabetes and is consistent with other studies showing a role of ABCC8 variants in pancreatic beta-cell function. However, our study focused on individuals from relatively few families. Ascertainment bias, family structure, and other interacting genes might have influenced our unexpected result. Additional studies are needed to replicate our observed deficit in beta-cell compensation in individuals heterozygous for ABCC8 variants. Likewise, the role of the GCK 3' variant in the reduced insulin sensitivity of obesity will require further study.

Prolonged fasting significantly changes nutrient oxidation and glucose tolerance after a normal mixed meal.

The aim of this study was to establish the experimental paradigm of fasting, followed by refeeding, to investigate individual differences in nutrient partitioning. Eight nonobese men were fed a normal meal (25% of daily energy requirements) on two occasions, after an overnight (13-h) fast and after a prolonged (72-h) fast. During the entire fasting period, subjects were resident in a whole room indirect calorimeter, and blood samples were drawn periodically. Because no other food was consumed over the 12 h after either meal, negative energy balance was observed after the overnight and prolonged fast. Postprandial carbohydrate oxidation was significantly reduced after the 72- vs. 13-h fast (P < 0.0001), whereas fat oxidation was significantly increased (P < 0.0001). Interestingly, carbohydrate balance was positive after the prolonged fast but negative after the overnight fast (24 +/- 17 vs. -57 +/- 16 g/12 h, respectively; P < 0.001), whereas fat balance was negative under both conditions (-78 +/- 7 vs. -47 +/- 8 g/12 h, respectively; P < 0.002). With 72 h of fasting, the glucose and insulin excursions in response to the mixed meal were significantly greater compared with the 13-h fast (P < 0.001). In conclusion, prolonged fasting resulted in a significant decrease in carbohydrate oxidation and an increase in fat oxidation, after a normal mixed meal, in healthy men. This was associated with a significant decrease in glucose tolerance. Because circulating free fatty acids were greatly elevated at all times after the prolonged fast, these may be mediating some of the changes in postprandial metabolism.

Effects of red wine, tannic acid, or ethanol on glucose tolerance in non-insulin-dependent diabetic patients and on starch digestibility in vitro.

This study examines the effect of moderate intake of red wine, tannic acid, or ethanol during a meal in type 2 diabetic patients and the influence of tannic acid on the digestibility of starch by alpha-amylase. Thirty non-insulin-dependent diabetes mellitus (NIDDM) patients aged 53 +/- 6 years were studied (in vivo study) 10 of whom received red wine (200 mL), 10 tannic acid (150 mg), and 10 ethanol (16 g) with their midday meal (600 calories, 65 g carbohydrate, 20 g lipid, and 34 g protein). All patients were tested on two occasions (water or placebo v wine, alcohol, or tannic acid). The influence of tannic acid (0.25, 0.5, and 1 mg) on the digestibility of starch (100 mg) by alpha-amylase (100 U) was tested in vitro by sequential incubation at 37 degrees C (in vitro study). The maximum glucose excursion after lunch was 2.6 +/- 0.8 mmol/L at 90 minutes (T90) for water and 1.8 +/- 0.9 mmol/L at T90 for red wine taken with the meal. The values at T60 and T90 were significant (P < .01). Comparable results were obtained with tannic acid alone (nonalcoholic component of wine): the maximum glucose excursion after lunch was 2.76 +/- 0.9 mmol/L at T120 for placebo and 1.97 +/- 0.9 mmol/L at T90 for tannic acid (P < .01); no difference in glucose and insulin excursion was observed between water and ethanol. No interaction between tannic acid and starch was observed in the in vitro experiments, although after preincubation of alpha-amylase with tannic acid, digestion was slowed in a dose-dependent manner (6.1 +/- 1.1 minutes for 0.25 mg tannic acid and 13.1 +/- 1.59 minutes for 1 mg tannic acid). Drinking red wine with a meal did not increase blood glucose in NIDDM patients, and led to a slight decrease in some instances. The effect appeared to be mediated by the nonalcoholic compounds in wine such as tannic acid. Ethanol itself had no effect on plasma glucose or insulin levels.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

1.Glucagon-like peptide-1 (7-36) amide (GLP-1) is released into the circulation after meals and is the most potent physiological insulinotropic hormone in man. GLP-1 has the advantages over other therapeutic agents for Type 2 diabetes of also suppressing glucagon secretion and delaying gastric emptying. One of the initial abnormalities of Type 2 diabetes is the loss of the first-phase insulin response, leading to postprandial hyperglycaemia.2. To investigate the therapeutic potential of GLP-1 in Type 2 diabetes, six patients were entered into a 6-week, double-blind crossover trial during which each received 3 weeks treatment with subcutaneous GLP-1 or saline, self-administered three times a day immediately before meals. A standard test meal was given at the beginning and end of each treatment period.3.GLP-1 reduced plasma glucose area under the curve (AUC) after the standard test meal by 58% (AUC, 0-240 min: GLP-1 start of treatment, 196+/-141 mmol.min-1.l-1; saline start of treatment, 469+/-124 mmol.min-1.l-1; F=16.4, P<0.05). The plasma insulin excursions were significantly higher with GLP-1 compared with saline over the initial postprandial 30 min, the time period during which the GLP-1 concentration was considerably elevated. The plasma glucagon levels were significantly lower over the 240-min postprandial period with GLP-1 treatment. The beneficial effects of GLP-1 on plasma glucose, insulin and glucagon concentrations were fully maintained for the 3-week treatment period. 4. We have demonstrated a significant improvement in postprandial glycaemic control with subcutaneous GLP-1 treatment. GLP-1 improves glycaemic control partially by restoring the first-phase insulin response and suppressing glucagon and is a potential treatment for Type 2 diabetes.

Hypoleptinemia in Women Athletes

The possibility that chronic nutritional deficiency alters leptin regulation and its link to reproductive function was investigated by determining serum leptin levels during a 24-h period with controlled nutrient intake in highly trained athletes with and without menstrual cyclicity and in BMI-matched cycling sedentary controls (n = 8 per group). Our data show that 24th leptin levels were reduced equally (3-fold, P < 0.001) in both cyclic and amenorrheic athletes as compared to controls. Low leptin levels in the athletic groups were consistent with their reduction in body fat (r = 0.91, P < 0.0001) relative to BMI, but were also influenced by the presence of low insulin (r = 0.70, P < 0.001) and elevated cortisol (r = -0.65, P < 0.001) levels. A diurnal pattern of 24h leptin levels, with an approximate 50% rise (P < 0.001) from nadir (0900h) to peak (0100h), was present in normally cycling athletes and controls and was strikingly absent in amenorrheic athletes. The absolute increase in leptin levels from nadir to peak was directly related to insulin excursions in response to meals (r = 0.60, P = .002) and inversely related to the amplitude of the 24h cortisol rhythm (r = -0.70, P = .0002). These findings are consistent with a link between the functionality of adipocytes, nutritional status, and integrity of the reproductive axis in humans.

Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea.

The possibility that chronic nutritional deficiency alters leptin regulation and its link to reproductive function was investigated by determining serum leptin levels during a 24-h period with controlled nutrient intake in highly trained athletes with and without menstrual cyclicity and in BMI-matched cycling sedentary controls (n = 8 per group). Our data show that 24th leptin levels were reduced equally (3-fold, P < 0.001) in both cyclic and amenorrheic athletes as compared to controls. Low leptin levels in the athletic groups were consistent with their reduction in body fat (r = 0.91, P < 0.0001) relative to BMI, but were also influenced by the presence of low insulin (r = 0.70, P < 0.001) and elevated cortisol (r = -0.65, P < 0.001) levels. A diurnal pattern of 24h leptin levels, with an approximate 50% rise (P < 0.001) from nadir (0900h) to peak (0100h), was present in normally cycling athletes and controls and was strikingly absent in amenorrheic athletes. The absolute increase in leptin levels from nadir to peak was directly related to insulin excursions in response to meals (r = 0.60, P = .002) and inversely related to the amplitude of the 24h cortisol rhythm (r = -0.70, P = .0002). These findings are consistent with a link between the functionality of adipocytes, nutritional status, and integrity of the reproductive axis in humans.

Cyclo(His-Pro) augments the insulin response to oral glucose in rats.

Cyclo(His-Pro) (CHP) is a gut-brain peptide found in rat and man. Since plasma levels of CHP are altered by oral glucose ingestion, we wondered whether exogenous CHP might alter the insulin response to oral glucose ingestion. To this end, rats were given 3g/kg oral glucose load with either saline or increasing doses of CHP and plasma levels of insulin, C-peptide and glucose were measured. We found mean insulin but not C-peptide excursions and area under the insulin but not C-peptide response curves (AUC) were significantly higher in the CHP groups than controls despite similar glucose responses. In summary, these data show that in rats receiving oral glucose, CHP causes higher insulin excursions without any change in C-peptide suggesting that CHP may decrease hepatic insulin clearance.

Hypoleptinemia in Women Athletes: Absence of a Diurnal Rhythm with Amenorrhea

The possibility that chronic nutritional deficiency alters leptin regulation and its link to reproductive function was investigated by determining serum leptin levels during a 24-h period with controlled nutrient intake in highly trained athletes with and without menstrual cyclicity and in BMI-matched cycling sedentary controls (n = 8 per group). Our data show that 24 h leptin levels were reduced equally (3-fold, P<0.001) in both cyclic and amenorrheic athletes as compared to controls. Low leptin levels in the athletic groups were consistent with their reduction in body fat (r=0.91, P<0.0001) relative to BMI, but were also influenced by the presence of low insulin (r=0.70, P<0.001) and elevated cortisol (r=−0.65, P <0.001) levels. A diurnal pattern of 24 h leptin levels, with an approximate 50% rise (P<0.001) from nadir (0900 h) to peak (0100 h), was present in normally cycling athletes and controls and was strikingly absent in amenorrheic athletes. The absolute increase in leptin levels from nadir to peak was directly related to insulin excursions in response to meals (r=0.60, P=.002) and inversely related to the amplitude of the 24 h cortisol rhythm (r=−0.70, P=.0002). These findings are consistent with a link between the functionality of adipocytes, nutritional status, and integrity of the reproductive axis in humans.

Metabolic response to meal eating and extended overnight fast in twin gestation

OBJECTIVE: Our purpose was to compare the metabolic response to normal meal eating and the vulnerability to starvation ketosis in twin versus singleton gestation. STUDY DESIGN: Data are reported on 10 twin and 10 singleton nondiabetic gestations enrolled in a 40-hour metabolic study. Singletons were age (±5 years) and prepregnancy weight (±10% ideal body weight) matched with twins. The diet (35 kcal/kg ideal body weight for singletons, 40 kcal/kg ideal body weight for twins) was distributed as one fifth at 8 AM, two fifths at 1 PM, and two fifths at 6 PM. An overnight fast was extended until noon the following day. Glucose and β-hydroxybutyrate measurements were made hourly except at night, when they were made every 2 hours. Insulin values were obtained before and after dinner and on the day when breakfast was delayed. RESULTS: The glucose, β-hydroxybutyrate, and insulin excursions in response to meal eating from 8 AM to 12:00 noon on day 1 were similar in twin and singleton pregnancies (analysis of variance for repeated measures, p < 0.05). On day 2, when breakfast was delayed, a progressive decrement in glucose was observed in both twins and singletons (p = 0.4682). Concurrently, there was a progressive rise in β-hydroxybutyrate in both twins and singletons, which was significantly greater for twins compared with singletons (p = 0.002). CONCLUSIONS: These data indicate that twin gestations are more vulnerable to the accelerated starvation of late normal pregnancy than singletons are in spite of additional caloric intake. We speculate that the observed difference may be the result of the increased metabolic demands of twin gestation. (Am J Obstet Gynecol 1996;175:917-21.)

Effect of acarbose on glucose homeostasis, lipogenesis and lipogenic enzyme gene expression in adipose tissue of weaned rats.

Acarbose is a potent intestinal glucosidase inhibitor which could have an anti-obesity property by reducing postprandial plasma glucose and insulin levels, potentially responsible for high rates of lipid synthesis in adipose tissue. We have tested this hypothesis by studying rats during the weaning period, when the lipogenic capacity of the adipose tissue develops. Rats were treated from age 19 days onwards with acarbose (10 mg/100 g diet) and studied at age 30 days. Acarbose was efficient in reducing postprandial excursions of both blood glucose and plasma insulin. Acarbose-treated rats behave like rats continuously infused with glucose with no metabolic signs of carbohydrate deprivation since gluconeogenesis was not activated. There was no massive caecal fermentation of carbohydrate since volatile fatty acids did not significantly increase in the portal blood. One of the most striking features of the acarbose-treated rats was the reduction of adipose tissue weight due to a reduced adipocyte size. This was concomitant with a reduced lipogenic capacity from glucose in isolated adipocytes under insulin stimulation. The activity of fatty acid synthase and acetyl-CoA carboxylase was decreased concomitantly with a reduced expression of their specific mRNA. This study allows the conclusion that postprandial hyperinsulinaemia and hyperglycaemia have a major role in the control of expression of lipogenic enzymes and thus on adipose tissue lipogenic capacity.

Glucose tolerance test periodicity as a descriptor of glucose tolerance abnormality

The periodicity of the standard 100-g glucose tolerance test (GTT) was examined in a prospective study of 194 pregnant patients to determine how well gestational diabetes could be identified. A simplified formula, the GTT periodicity, was used to estimate the time for the GTT curve to return to the fasting level. One hundred one study subjects had all normal glucose values by the National Diabetes Data Group criteria (0-abnormal group), 47 had one value greater than normal (1-abnormal group), and 46 had more than one value abnormal or gestational diabetes. The 0-abnormal patients had a significantly shorter GTT periodicity than did 1-abnormal or gestational diabetic mothers (3.6 versus 4.8 versus 6.6 hours, respectively; P less than .04). Calculating the periodicity for the corresponding insulin excursions yielded significantly increasing values in a graduated fashion for each group (5.2 versus 6.9 versus 9.6 hours, respectively; P less than .05). Examination of the oscillation of the GTT curve about the fasting level allows a physiologic description of normal and abnormal glucose responses in pregnancy. Furthermore, our findings suggest that glucose and insulin periodicities are useful predictors of gestational diabetes in patients with positive screening.

Regulation of net hepatic glucose uptake in vivo.

Increases in the glucose level in the absence of the portal signal or changes in insulin elicits little if any glucose uptake by the liver. NHGU is augmented by a rise in insulin (or drop in glucagon) and is further stimulated by the presence of a portal signal. Under postprandial conditions, NHGU will depend on the dynamic interaction between the pancreatic hormones, glucose and the portal signal. Moreover, in a simulated postprandial environment, the quantitative impact of the portal signal is at least as important as that of insulin. The presence of the portal signal should be of physiologic benefit because it will allow adequate net removal of glucose by the liver without requiring excessive excursions of insulin and glucose. The metabolic fate of ingested glucose within the liver is still controversial. It appears that the liver will remove 30-40% of the glucose that enters the portal vein following an oral glucose load and will replete its glycogen stores by both direct and indirect pathways. Whether the three-carbon precursors utilized by the indirect route are of hepatic or peripheral origin remains a matter of debate. Studies are under way to elucidate whether the hepatic response to the portal signal involves the autonomic nervous system, the nature of the interaction of the portal signal and insulin, and the metabolic fate of glucose removed by the liver in response to this signal.

Use of a more physiologic oral glucose solution during testing for gestational diabetes mellitus.

A lower osmolar oral glucose solution (50 g glucose in 450 mL fluid, 0.62 mol/L) was administered in addition to the standard hyperosmolar oral glucose solution (100 g glucose in 300 mL fluid, 1.85 mol/L) for oral glucose tolerance testing 1 week apart to 102 pregnant women. The standard oral glucose solution creates delayed gastric emptying and is associated with frequent nausea and vomiting. Results using the modified, lower osmolar glucose solution, when compared to the standard hyperosmolar glucose solution showed (1) statistically equivalent glucose excursion values 30 minutes after ingestion, (2) statistically significant decreased plasma glucose values greater than or equal to 60 minutes, (3) no statistically significant difference in insulin excursion values 30 minutes after ingestion, (4) equal area under the curve for glucose at 30 minutes using either solution, and (5) a markedly decreased incidence of nausea and vomiting. These data suggest that the modified, lower osmolar glucose solution empties rapidly from the stomach and allows the glucose to be absorbed and enter the peripheral circulation in an expeditious manner.

Hepatic Denervation Alters the Disposition of an Enteral Glucose Load in Conscious Dogs

The aim of this study was to establish the role of nerves to the liver in the disposal of an enteral glucose load. Dogs underwent a laparotomy during which the nerves to the liver were either left intact (C; n = 10) or removed (DN; n = 10). Absence of measurable liver norepinephrine was used to indicate completeness of denervation. Four weeks following surgery, 18-h fasted conscious dogs were given a glucose load (0.7 g/kg body weight) by gavage, and arterial blood samples were drawn over a 180-min period. The glucose and insulin excursions from baseline (incremental area) were 29% and 22% greater (P greater than 0.05) in DN than in C, respectively. Resting blood lactate levels were similar between groups, but they increased significantly more (P less than 0.05) following the administration of the glucose load in DN (peak change from resting level was 376 +/- 90 mumol/L in C and 728 +/- 81 mumol/L in DN). No significant differences between groups in glucagon, glycerol or alanine concentration were evident either prior to or following glucose administration. These data demonstrate that hepatic nerves can influence the substrate and hormone environment following an enteral glucose load.

Effect of trestatin, an amylase inhibitor, incorporated into bread, on glycemic responses in normal and diabetic patients

The effect of incorporating the pancreatic alpha-amylase inhibitor trestatin into bread on postprandial plasma glucose and insulin excursions was tested in healthy volunteers and non-insulin-dependent diabetic patients. At both dose levels of trestatin (3 and 6 mg/75 g starch) the peak values of plasma glucose and insulin were reduced markedly (compared with placebo) after the ingestion of 75 g starch in the form of bread. In healthy control subjects as well as in diabetic patients, trestatin produced significantly lower insulin excretions but also significant reductions in incremental plasma glucose areas in a dose-dependent fashion. It is concluded that it is technologically feasible to incorporate trestatin into starchy foods without loss of activity or impairment of taste. Furthermore, the positive effect of trestatin on glycemic and insulinemic responses in diabetics and the lack of serious side effects offer a great potential in the dietary treatment of diabetic patients.

Levels of Glucose and Insulin during Twenty-Four Hours in Hyperprolactinemic Women with Pituitary Microadenoma

Excursions of plasma glucose and insulin throughout the 24-hour metabolic clock were evaluated in hyperprolactinemic women with pituitary microadenoma. The glucose response to food intake and 24-hour excursion of plasma glucose were not altered in hyperprolactinemic women compared to normal women. Premeal and 24-hour insulin levels were significantly increased in hyperprolactinemic women, though fasting insulin levels were not. Postprandial insulin increments appeared to be more sustained in these patients compared to normal women, though the difference was not statistically significant. And therefore the increased 24-hour concentration of insulin in hyperprolactinemic women appears to be due to the sustained insulin response to meals and increased premeal insulin levels. A slight resistance to insulin was observed in hyperprolactinemic women. That the 24-hour excursion of plasma glucose is not altered in hyperprolactinemic women in the face of decreased sensitivity to insulin may be accounted for by the increased insulin secretion.

Reduction of postprandial blood glucose by theα-glucosidase inhibitor Miglitol (BAY m 1099) in Type II diabetes

The dose-dependency of the effects of the alpha-glucosidase inhibitor Miglitol (Bay m 1099) was investigated in 8 Type II diabetic patients. Administration of increasing doses of Miglitol once daily in the morning on four consecutive days concomitantly with a standardized meal containing 50 g starch led to a dose-dependent reduction in the maximal increase in the postprandial blood glucose level and in postprandial incremental AUC of blood glucose. The latter was significant for 50, 100, 75 and 200 mg Miglitol. Bay m 1099 also markedly retarded the appearance of the peak postprandial blood glucose concentration, which indicates delayed carbohydrate absorption. Serum insulin levels, documented as incremental AUCs of the serum insulin excursions, were not reduced dose dependently, because of the impaired insulin secretory capacity of the patients.

Glucose Suppression of Glucagon: Relationship to Pancreatic Beta Cell Function?

Plasma insulin and glucagon responses during 4h, 50 g oral glucose tolerance tests were assessed in 35 adults subdivided into four groups: weight-matched obese control and obese diabetic; lean control and lean, insulin-requiring diabetic subjects. Average basal glucagon levels were not significantly different among the four groups despite relative fasting hyperinsulinemia in obese subjects. Patterns of plasma glucagon suppression and plasma insulin excursions after oral glucose loading differentiated the four groups from one another. In obese controls, brisk hyperinsulinemia was associated with sustained suppression of glucagon from 60 through 240 min. In lean controls, significant glucagon suppression also occurred at 60 min but was not sustained. Subnormal plasma insulin increments during the initial 60 min of the test in obese diabetic subjects was attended by a delayed onset of glucagon suppression at 90 min which was also unsustained. In lean diabetic subjects no suppression of glucagon was observed ...