The effect of insulin deprivation on fasting levels of 5000 dalton gastric inhibitory polypeptide in type 1 (insulin-dependent) diabetics

To investigate whether metabolic decompensation has an effect on gastric inhibitory polypeptide (GIP), 8 fasting male type 1 diabetics were deprived of insulin for 12 h. An overnight insulin infusion aiming at normoglycaemia was stopped at 08.00 h. During the following 12 h blood glucose increased from 7.0 +/- 0.4 to 14.9 +/- 1.0 mmol/l, P less than 0.01, 3-hydroxy-butyrate from 0.18 +/- 0.07 to 4.00 +/- 0.74 nmol/1, P less than 0.01, and immunoreactive GIP (IR-GIP) from 16.7 +/- 2.6 to 21.9 +/- 2.9 pmol/1, P less than 0.05. The antiserum employed, R65, only measures 5000 dalton IR-GIP. The final IR-GIP concentrations were not significantly different from fasting IR-GIP concentrations in 13 normal male subjects (17.4 +/- 1.5 pmol/1). Short term insulin deprivation therefore is associated with a slight increase in fasting IR-GIP concentrations. Whether this modest increase in IR-GIP significantly enhances insulin secretion is unknown.     

Diminished immunoreactive gastric inhibitory polypeptide response to a meal in newly diagnosed type I (insulin-dependent) diabetics

The release of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to a standard meal was examined in 10 normal subjects and 15 type I (insulin-dependent) diabetics 7 days (test I), 14 days (test II), and 3 months (test III) after time of diagnosis. During all three tests, the diabetics had significantly lower plasma IR-GIP concentrations than the controls from 15-90 min after the standard meal. The IR-GIP response in the diabetics measured as the integrated area under the response curve corresponded to 70% of that of normal subjects. beta-cell function evaluated from the C-peptide response to the meal increased significantly from test I to test III whereas the IR-GIP response was similar during all three tests. As GIP is known to potentiate glucose-induced insulin secretion and possibly the biosynthesis of insulin, the low IR-GIP responses in subjects with type I diabetes may significantly influence insulin levels and hyperglycemia.     

C-peptide response to oral glucose and its clinical role in elderly people.

C-Peptide response to oral glucose was measured in 45 elderly diabetics, in whom final treatment was established on clinical grounds during a 16-18 months follow-up. The diabetic patients comprised 19 ultimately classified as insulin-dependent (IDD) (group 1) and 26 regarded as non-insulin-dependent (NIDD) (group 2). Fifteen matched controls (group 3) and 15 young controls (group 4) were similarly studied. Fasting C-peptide values were lower in groups 1 and 2 (1.48 +/- 0.39 and 2.14 +/- 0.22 ng/ml; mean +/- SEM, respectively) compared with groups 3 and 4 (2.51 +/- 0.16 and 2.71 +/- 0.20 ng/ml, respectively) (p less than 0.001). Peak C-peptide levels were reached at 30 min in healthy young and at 60 min in healthy elderly. All non-diabetic control subjects showed a peak of at least 6.5 ng/ml and an increment of at least 4 ng/ml. The ratio of C-peptide increment/blood glucose increment (100 delta CP/delta BG) at 60 min derived to assess beta-cell function was at least 90 in all healthy subjects. The ratio was less than 10 in 68% of IDD but in only 27% of NIDD patients (p less than 0.01). The 100 delta CP/delta BG was inversely related to the prevailing fasting blood glucose (FBG) (p less than 0.001). These findings suggest that C-peptide response to oral glucose may be a useful test in certain elderly diabetic patients whose insulin dependence is in question.     

GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING FACTOR IN DIABETIC MEN

Increased plasma concentrations of growth hormone (GH) are reported in diabetes and it is suggested that this may be important in the development of complications. We have investigated fasting GH levels and the response to 100 micrograms i.v. growth hormone releasing factor, GRF(1-29)NH2, in age-matched men: six normal weight controls, six obese controls, six insulin-dependent diabetics, six normal weight non-insulin dependent diabetics and six obese non-insulin dependent diabetics. None of the diabetic men had clinical evidence of diabetic complications. Fasting GH values did not differ significantly between the five groups. The peak GH response to GRF was similar in the controls, insulin-dependent diabetics (IDD) and non-insulin dependent (NIDD) normal weight diabetics (mean peak +/- SEM: controls 25.5 +/- 5 mU/l, IDD 26.5 +/- 6 mU/l, NIDD 19.7 +/- 5 mU/l) but was significantly reduced in the two obese groups (obese 6.4 +/- 3 mU/l, obese diabetics 4.5 +/- 1 mU/l, P less than 0.01). This impairment of GH secretion was unrelated to either fasting plasma insulin or glucose concentration. We conclude that our results do not confirm the previous reports of abnormal GH secretion in diabetes but do demonstrate a markedly impaired GH response to GRF to be a feature of obesity.     

Relation of immunoreactive gastric inhibitory polypeptide to changes in glycaemic control and B cell function in type 1 (insulin-dependent) diabetes mellitus

The effect of strict glycaemic control on plasma immunoreactive gastric inhibitory polypeptide (IR-GIP) concentrations and pancreatic B cell function as estimated by plasma C-peptide was evaluated in 14 Type 1 (insulin-dependent) diabetics. The effect was estimated by giving a test meal before (test 1) and after (test 2) 1 week with near normal blood glucose control (mean blood glucose 6.7 +/- 0.2 mmol/l) and again 3 weeks later (test 3) in the outpatient clinic. The glycaemic control was significantly improved at test 2 and test 3 compared with that of test 1. The IR-GIP concentrations before and after the meals were similar at all three tests and not different from those found in 21 normal controls. In 8 patients with a significant B cell response at test 1, B cell function was significantly improved both at test 2 and test 3 but no change in fasting or post-prandial IR-GIP concentrations was found and no correlation between B cell function and IR-GIP existed. We conclude that strict glycaemic control improves B cell function but does not modulate plasma IR-GIP concentrations. Factors other than GIP seem to be of greater importance in determining the magnitude of B cell function in Type 1 diabetes.     

Clinical application of the 24-H urinary C-peptide excretion rate and its relationship to metabolic control in diabetics

Summary In this study, we evaluated in normal subjects, insulin-dependent (IDD) and non-insulin-dependent (NIDD) diabetics, the diurnal urinary C-peptide excretion rate (CPR-U) and its relationship to serum C-peptide concentration and glucose:C-peptide molar ratio, and to the common parameters of metabolic control. The CPR-U (and CPR-U/g creatinine) were significantly lower in IDD and higher in NIDD compared to control subjects. Moreover, a good and significant correlation with serum C-peptide concentrations and the glucose:C-peptide ratio in diabetic subjects as well as in controls and diabetics considered together was found. A slight but significant correlation was present in diabetic subjects between CPR-U and body mass index (r=0.45), 24-h glycosuria (r=−0.36), HbA1 levels (r=−0.31), post-prandial glucose concentrations (r=−0.26) and per cent glucose variation after each meal (r=−0.34). No differences were found in CPR-U and the degree of metabolic control between obese and non-obese NIDD. In conclusion, CPR-U may be a useful and simple method of defining the secretory activity of the B-cell. Metabolic control in diabetics is slightly correlated to the degree of B-cell function as evaluated by the diurnal excretion rate of C-peptide in urine. Part of this paper was presented at the National Meeting of the Italian Diabetes Association, Bari, May 27–29, 1982.     

Persistent abnormalities of the metabolism of an oral glucose load in insulin-treated type I diabetics

We have compared disposal of an oral glucose load in 12 normal subjects and 10 c-peptide-negative, type I-diabetic subjects, who were treated with insulin (by overnight intravenous insulin infusion followed by a dose of subcutaneous insulin prior to the oral glucose load) to achieve a blood glucose profile that approximated the glucose intolerance commonly seen in insulin-treated diabetics. We used a combination of the dual-isotope and forearm techniques, together with whole-body indirect calorimetry, to quantify the various determinants of glucose tolerance. The diabetic subjects had impaired glucose tolerance in that, despite similar fasting plasma glucose levels (5.46 +/- 0.17 mmol/L v 5.35 +/- 0.10 mmol/L in the normal subjects), they had a higher peak glucose (14.3 +/- 1.2 mmol/L v 10.0 +/- 0.7 mmol/L P less than .01) and area under the glucose curve (2,483 +/- 197 mmol.min/L v 1,525 +/- 43 mmol.min/L P less than .001). Up to 120 minutes after the oral glucose load, the amount of glucose entering the systemic circulation exceeded that leaving by 14.6 +/- 2.3 g in the diabetics and only by 2.6 +/- 0.5 g in the normal subjects (P less than .001), accounting for the higher plasma glucose peak in the diabetics. Total systemic glucose appearance rates were significantly greater in the diabetics between 60 and 120 minutes, and endogenous glucose production suppressed more slowly in diabetics than in the normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lowering of fasting and food stimulated serum immunoreactive gastric inhibitory polypeptide (GIP) by glucagon.

The effect of intravenous glucagon infusion on serum levels of immunoreactive GIP (IR-GIP), insulin (IRI), gastrin (IRG), and on blood glucose has been investigated in six healthy volunteers in the fasting state and during ingestion of a mixed standard meal. Glucagon (500 ng/kg/min) lowered significantly serum levels of IR-GIP and IRG below the fasting values and increased the levels of IRI and blood glucose. Glucagon (50 ng/kg/min) infused 30 minutes before and continued 90 minutes after ingestion of a test meal abolished the IR-GIP response, suppressed significantly the IRG response, and left the IRI response unchanged. The same glucagon dose infused 60 minutes after ingestion of the test meal decreased significantly the raised levels of IR-GIP and IRG to fasting levels without changing IRI values. It is concluded that exogenous glucagon inhibits Gip release at the level of the GIP-producing cells.     

Immunoreactive gastric inhibitory polypeptide response to a meal during the first eighteen months after diagnosis of type 1 (insulin dependent) diabetes mellitus

The changes in plasma concentrations of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to a standard meal were examined in 21 normal subjects and 15 Type 1 (insulin dependent) diabetic patients 7 days, 14 days, and 3, 6, 9, 12, and 18 months after time of diagnosis. During the first 4 tests significantly lower plasma IR-GIP concentrations were found in the diabetic patients after the standard meal. At 9 months and during the remaining tests there was no difference in IR-GIP concentrations between the diabetic and the normal subjects. The IR-GIP response was normalized faster if the diabetic patients were treated with initial short term intensive insulin therapy than if they were treated conventionally with 1 or 2 daily injections of insulin. beta-Cell function, evaluated by the C-peptide response to the meal, increased significantly during the first 3 months. After 3 months maximal beta-cell function was found while the corresponding IR-GIP responses were significantly lower than those of the normal subjects. Thereafter beta-cell function declined gradually and significantly, coinciding with the normalization of the IR-GIP response. No individual covariation between IR-GIP and beta-cell function during the 18 months was found in any patient. The IR-GIP response to a meal was diminished at the onset of Type 1 (insulin dependent) diabetes mellitus. After the start of insulin therapy the response improved, perhaps as a function of the quality of metabolic control, and within a year it was comparable to that of normal subjects. Lack of endogenous GIP therefore does not explain the diminished beta-cell function in Type 1 diabetes a few months after onset of the disease. No causal relationship between the changes in beta-cell function and IR-GIP during the first 18 months after the onset of the disease seems to exist.     

Hyperinsulinemia in the physiologic range is not superior to short-term fasting in suppressing insulin secretion in obese men

The negative-feedback control exerted by plasma insulin on beta-cell insulin release in normal-weight and obese subjects is still a matter of debate. Subjects submitted to a euglycemic insulin clamp undergo a suppression of insulin secretion that is due to both the infused insulin and the 2- to 3-hour fast during the procedure. We elected to elucidate the role of physiologic hyperinsulinemia per se in the insulin negative autofeedback in obese men. Ten men with massive uncomplicated obesity (age, 18 to 37 years; body mass index [BMI], 41 +/- 1.15 kg/m2) and 6 normal-weight healthy men (age, 22 to 30 years; BMI, 22 +/- 0.28 kg/m2) underwent 2 studies in random order: (1) a euglycemic-hyperinsulinemic glucose clamp with an insulin infusion rate of 1 mU/kg/min and (2) a control study with saline infusion. Serum C-peptide concentrations were significantly higher in obese versus control subjects at baseline (2.54 +/- 0.178 v 1.63 +/- 0.256 ng/mL, P < .05). Exogenous insulin infusion significantly suppressed serum C-peptide at steady state ([SS] last 30 minutes of insulin or saline infusion) in controls (mean of the last 4 measurements from 120 minutes to 150 minutes, 0.86 +/- 0.306 ng/mL, P < .05 vbaseline) but not in obese patients (2.03 +/- 0.26 ng/mL, nonsignificant [NS] v baseline). During the saline infusion studies, C-peptide levels slightly and similarly declined over time in both groups (2.71 +/- 0.350 at baseline v 2.31 +/- 0.300 ng/mL at SS in obese patients, NS, and 1.96 +/- 0.189 v 1.62 +/- 0.150 ng/mL in controls, NS). This study shows that in obese men hyperinsulinemia within the postprandial range is not superior to a 2.5-hour fast for the suppression of beta-cell activity, suggesting an impairment of the insulin negative autofeedback in this clinical condition.     

Similar insulin secretory response to a gastric inhibitory polypeptide bolus injection at euglycemia in first-degree relatives of patients with type 2 diabetes and control subjects

Insulin secretion following the intravenous infusion of gastric inhibitory polypeptide (GIP) is diminished in patients with type 2 diabetes and at least a subgroup of their first-degree relatives at hyperglycemic clamp conditions. Therefore, we studied the effects of an intravenous bolus administration of GIP at normoglycemic conditions in the fasting state. Ten healthy control subjects were studied with an intravenous bolus administration of placebo, and of 7, 20, and 60 pmol GIP/kg body weight (BW), respectively. Forty-five first-degree relatives of patients with type 2 diabetes and 33 matched control subjects were studied with (1) a 75-g oral glucose tolerance test (OGTT) and (2) an intravenous bolus injection of 20 pmol GIP/kg BW with blood samples drawn over 30 minutes for determination of plasma glucose, insulin, C-peptide, and GIP. Statistical analysis applied repeated-measures analysis of variance (ANOVA) and Duncan's post hoc tests. Insulin secretion was stimulated after the administration of 20 and of 60 pmol GIP/kg BW in the dose-response experiments (P <.0001). GIP administration (20 pmol/kg BW) led to a significant rise of insulin and C-peptide concentrations in the first-degree relatives and control subjects (P <.0001), but there was difference between groups (P =.64 and P =.87, respectively). Also expressed as increments over baseline, no differences were apparent (Delta(insulin), 7.6 +/- 1.2 and 7.6 +/- 1.6 mU/L, P =.99; Delta(C-peptide), 0.35 +/- 0.06 and 0.38 +/- 0.08 ng/mL, P =.75). Integrated insulin and C-peptide responses after GIP administration significantly correlated with the respective insulin and C-peptide responses after glucose ingestion (insulin, r = 0.78, P <.0001; C-peptide, r = 0.35, P =.0015). We conclude that a reduced insulinotropic effect of GIP in first-degree relatives of patients with type 2 diabetes cannot be observed at euglycemia. Therefore, a reduced GIP-induced insulin secretion in patients with type 2 diabetes and their first-degree relatives at hyperglycemia is more likely due to a general defect of B-cell function than to a specific defect of the GIP action.     

Gastric inhibitory polypeptide (GIP) hypersecretion in obesity depends on meal size and is not related to hyperinsulinemia

Summary The response of immunoreactive gastric inhibitory polypeptide (IR-GIP), immunoreactive insulin (IRI) and immunoreactive C-peptide (IR-C-peptide) to the ingestion of mixed liquid test meals containing 1031 kcal (550 ml) and 422 kcal was studied in 17 obese and 17 normal weight control subjects. When the 422 kcal load was ingested in a volume of 550 ml, the plasma IR-GIP response was significantly greater than in a volume of 225 ml at 15 and 30 min in lean and obese subjects, but the total integrated IR-GIP response was not significantly different between the obese and lean group. Also intraduodenal infusion of 150 ml (280 kcal) of the test meal elicited identical plasma IR-GIP concentrations in lean and obese subjects. An exaggerated IR-GIP response in obese subjects was seen only following the 1031 kcal load (integrated IR-GIP response: 23.6±1.9 in lean subjectsvs 50.3±3.8 nmol/1/180 min in obese subjects; p<0.01). The IRI response was always significantly greater in obese than in lean subjects and not related to the GIP response. Fasting plasma IR-C-peptide levels were significantly elevated in obese subjects (lean: 0.52±0.04; obese: 1.42±0.12 nmol/l; p<0.005), but the postprandial integrated IR-C-peptide responses in the obese and lean group were identical, indicating decreased hepatic insulin extraction in obesity. It is concluded that an exaggerated IR-GIP response in obesity occurs only after ingestion of a high calorie meal probably as consequence of an increased gastric emptying rate and that the hyperinsulinemic response of obese subjects is not attributable to GIP hypersecretion.     

Effect of graded intraduodenal glucose infusions on the release and physiological action of gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP) is the leading candidate for gut hormonal augmentation of insulin release. The release of its subspecies (mol wt, 5000 and 7500) and the physiological action of total immunoreactive GIP (IR-GIP) were investigated during isotonic glucose infusions at 75, 225, and 465 mg/min in nine volunteers. Each dose was infused intraduodenally and iv in the same volunteer. Intestinal augmentation of insulin release occurred during the high dose intraduodenal glucose infusion (P less than 0.001) but not during the lower doses. An elevation of 17-20 mg/dl in plasma glucose was required before this insulinotropic effect occurred (P less than 0.001). At increments of plasma glucose above 17 mg/dl, the augmentation of gut-mediated insulin release was dependent on the degree of hyperglycemia (r = 0.81; P less than 0.01). At each dose of intraduodenally administered glucose, IR-GIP was elevated within 20-40 min (P less than 0.01), remaining at a steady level until the infusion was stopped. The release of IR-GIP was elevated within 20-40 min (P less than 0.01), remaining at a steady level until the infusion was stopped. The release of IR-GIP was proportional to the intestinal glucose load but was unchanged from the basal level during iv glucose studies. The attained IR-GIP levels remained constant in each study despite large variations over time in plasma glucose and insulin concentrations. During intestinal glucose infusion, 58.7 +/- 4.1% of IR-GIP was accounted for by the 5000 mol wt subspecies and 17.3 +/- 3.5% was accounted for by the 7500 mol wt subspecies, with the remaining immunoreactivity found in the void volume of a Sephadex G-50 column. Relative proportions remained constant throughout the 4-h study. Thus, during glucose stimulation, the total IR-GIP released 1) is proportional to the absorbable luminal stimulus, 2) is independent of ambient plasma insulin and glucose levels, 3) is composed predominantly of the 5000 mol wt form, and 4) requires an elevation in plasma glucose of 17-20 mg/dl before it augments insulin release, but then stimulates insulin release in a fashion linearly dependent upon the increment in plasma glucose.     

Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients

AIMS/HYPOTHESIS: Glucagon-like-peptide-1 (GLP-1) is strongly insulinotropic in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas glucose-dependent insulinotropic polypeptide (GIP) is less effective. Our investigation evaluated "early" (protocol 1) - and "late phase" (protocol 2) insulin and C-peptide responses to GLP-1 and GIP stimulation in patients with Type II diabetes. METHODS: Protocol 1: eight Type II diabetic patients and eight matched healthy subjects received i.v. bolus injections of GLP-1(2.5 nmol) or GIP(7.5 nmol) concomitant with an increase of plasma glucose to 15 mmol/l. Protocol 2: eight Type II diabetic patients underwent a hyperglycaemic clamp (15 mmol/l) with infusion (per kg body weight/min) of either: 1 pmol GLP-1 (7-36) amide (n=8), 4 pmol GIP (n=8), 16 pmol GIP (n=4) or no incretin hormone (n=5). For comparison, six matched healthy subjects were examined. RESULTS: Protocol 1: Type II diabetic patients were characterised by a decreased "early phase" response to both stimuli, but their relative response to GIP versus GLP-1 stimulation was exactly the same as in healthy subjects [insulin (C-peptide): patients 59+/-9% (74+/-6%) and healthy subjects 62+/-5% (71+/-9%)]. Protocol 2, "Early phase" (0-20 min) insulin response to glucose was delayed and reduced in the patients, but enhanced slightly and similarly by GIP and GLP-1. GLP-1 augmented the "late phase" (20-120 min) insulin secretion to levels similar to those observed in healthy subjects. In contrast, the "late phase" responses to both doses of GIP were not different from those obtained with glucose alone. Accordingly, glucose infusion rates required to maintain the hyperglycaemic clamp in the "late phase" period (20-120 min) were similar with glucose alone and glucose plus GIP, whereas a doubling of the infusion rate was required during GLP-1 stimulation. CONCLUSION/INTERPRETATION: Lack of GIP amplification of the late phase insulin response to glucose, which contrasts markedly to the normalising effect of GLP-1, could be a key defect in insulin secretion in Type II diabetic patients.     

Reproducibility of the glucagon test

The influence of the fasting blood glucose (FBG) concentration on the beta-cell responsiveness to glucagon was studied twice in 9 insulin-dependent diabetic patients with residual beta-cell function. At a FBG of 7.7 +/- 0.3 mmol/l (mean +/- SEM) all patients displayed a preserved beta-cell function with a plasma C-peptide concentration of 0.25 +/- 0.03 nmol/l 6 min after an i.v. injection of glucagon. In contrast, at a FBG of 3.2 +/- 0.01 mmol/l 4 out of 9 patients would have been classified as not having an endogenous insulin secretion. All the patients had the lowest 6 min C-peptide concentration 0.06 +/- 0.01 nmol/l on the day with the lowest blood glucose concentration. The reproducibility of the glucagon test was assessed by comparing the results from two test days in 12 insulin-dependent, 9 non-insulin-dependent diabetic patients and 6 normal subjects. The 6 min plasma C-peptide concentration, the peak plasma C-peptide concentration, and the area under the plasma C-peptide curves were not different on the two test days in any subgroup. In all diabetic patients and normal subjects, the 6 min plasma C-peptide concentration (r = 0.93, coefficient of variation (CV) = 0.16), the peak plasma C-peptide concentration (r = 0.93, CV = 0.16) and the area under the plasma C-peptide curve (r = 0.94, CV = 0.16) were all significantly correlated. The results show that the prevailing FBG significantly affects the outcome of the glucagon test and confirm its reproducibility.     

Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8

The quantitative contribution of glucose-dependent insulinotropic polypeptide [gastric inhibitory polypeptide (GIP)] to the incretin effect after oral glucose (augmentation of insulin secretion over the degree that is explained by the glycemic rise) is not known. Therefore, hyperglycemic clamp experiments (8 mmol/L, corresponding to postprandial glucose concentrations) were performed in healthy volunteers, and synthetic human GIP was infused for 60 min at a rate (approximately 1.3 pmol/kg.min) that results in plasma GIP concentrations similar to those occurring after oral glucose loads of 75 g. The MCR for exogenous GIP was approximately 6 mL/kg.min; the decay after ceasing infusion was exponential with a t1/2 of about 18 min, and the resulting volume of distribution was about 140 mL/kg. At euglycemic (basal) plasma glucose concentrations (5.0 mmol/L) similar values were found. Insulin secretion was stimulated by hyperglycemia alone, but was greatly (2.3-fold based on C-peptide) potentiated by GIP infusions (P less than or equal to 0.001 for integrated incremental values). When integrated incremental responses over 120 min of GIP, immunoreactive insulin, and immunoreactive C-peptide were compared after oral glucose and during GIP infusions, no significant differences were found. Peak glucose concentrations after oral glucose (7.6 +/- 0.6 mmol/L) were similar to mean plasma glucose values during clamp experiments (8.2 +/- 0.1 mmol/L; P = 0.124). However, mean glucose concentrations after oral glucose were lower (6.0 +/- 0.3 mmol/L; P = 0.0004). Additional infusion of sulfated cholecystokinin-8 (25 pmol/kg.h) or the amino acid phenylalanine (1.7 mumol/kg.min) did not further stimulate insulin secretion and had no influence on the pharmacokinetics of exogenous GIP. It is concluded that human synthetic GIP is insulinotropic in man and that this activity may well explain a substantial part of the incretin effect after oral glucose. There is no interaction with cholecystokinin or phenylalanine in concentrations found after mixed meals.     

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.     

Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.     

A supplementary infusion of glucose-dependent insulinotropic polypeptide (GIP) with a meal does not significantly improve the beta cell response or glucose tolerance in type 2 diabetes mellitus

Newly diagnosed, previously untreated patients with type 2 diabetes mellitus (n = 6) were studied on two separate days after overnight fasts. On each day they were given a 500-kcal mixed meal plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (GIP) (0.75 pmol/kg/min) or control solution (CS) from 0 to 30 min in random order. Frequent measurements of plasma glucose, C-peptide, insulin and GIP concentrations were made. Fasting GIP levels were similar on both days. During the meal plus GIP infusion plasma GIP levels increased from a basal value of 7.6 +/- 1.5 pmol/1 to a peak of 88.6 +/- 5.4 pmol/1 at 30 min. Following the meal infusion of CS GIP increased from a fasting level of 10.3 +/- 1.2 pmol/1 to a significantly lower peak of 58.0 +/- 8.3 pmol/1 at 60 min. During the meal plus GIP infusion GIP levels were higher at 10-45 min and at 90 min (P less than 0.05-0.001). Fasting and postprandial glucose, C-peptide and insulin levels were, however, similar on both study day. A supplementary infusion of porcine GIP with a mixed meal did not significantly alter the beta cell response or glucose tolerance in this group of patients with type 2 diabetes mellitus.     

Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P <.001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P <.001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P =.055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.