Pulsatile insulin secretion in elderly patients with diabetes

Insulin pulsation is impaired in type 2 diabetes. GLP-1 increases pulsatile insulin secretion in these patients. We conducted these studies with the hypothesis that GLP-1 would enhance pulsatile insulin secretion and alter glucose metabolism in elderly patients with type 2 diabetes. Experiments were conducted in nine patients (age: 72+/-5 years; BMI: 27+/-3kg/m(2); diabetes duration: 7+/-3 years; HbA(1c): 6.6+/-0.9%). Subjects underwent three glucose clamp studies. The first was a euglycemic clamp to determine individual insulin clearance. In the second, GLP-1 was infused from 0-240min (0.75pM/kg/min) and glucose was maintained at fasting levels. The third was similar except that octreotide (30ng/kg/min) was infused with GLP-1 to suppress pulsatile insulin. Insulin and glucose were given to match levels during the second study. 3-(3)H-glucose was infused to allow calculation of hepatic glucose production and glucose disposal rates. There was no significant difference in measurements of pulsatile insulin secretion or hepatic glucose production and glucose disposal rates between the studies. Because there was no difference in pulsatile insulin between experiments, we could not test the effect of pulsatile insulin on glucose metabolism. Further studies are required to determine the impact of insulin pulses on glucose metabolism.     

Disruption of the pulsatile and entropic modes of insulin release during an unvarying glucose stimulus in elderly individuals.

Insulin is secreted in a pulsatile fashion with measurable orderliness (low entropy). Aging is characterized by alterations in pulsatile insulin release in the fasting state. We undertook the current studies to determine whether disruptions in pulsatile insulin release in response to sustained glucose infusion also accompany the age-related changes in carbohydrate metabolism. Healthy young (n = 10; body mass index, 23 +/- 1 kg/m2; age, 23 +/- 1 yr) and old (n = 10; body mass index, 24 +/- 1 kg/m2; age, 80 +/- 2 yr) volunteers underwent a 600-min hyperglycemic glucose clamp. During the entire 600 min, insulin was sampled every 10 min, and insulin release was evaluated by Cluster analysis. From 240-360 min, insulin was sampled every 1 min, and secretory pulse analysis was conducted using a multiparameter deconvolution technique. During the 1-min sampling interval, basal insulin secretion (P < 0.01), insulin production rate (P < 0.01), pulsatile mean and integrated insulin concentration (P < 0.01), insulin secretory burst mass (P < 0.01), and burst amplitude (P < 0.05) were reduced in the elderly. In addition, interpulse interval was increased in the aged (P < 0.05). In the 600-min studies, interpulse interval was greater in the aged (P < 0.01) and burst number (P < 0.01), basal concentration (P < 0.01), and burst increment (P < 0.05) were less. Approximate entropy, a measure of irregularity of insulin release, was increased in the aged, signifying the loss of orderliness of insulin secretion (P < 0.05). We conclude that in response to a sustained (10-h) glucose infusion, normal aging is characterized by a reduction in mass and amplitude of rapid insulin pulses and a decrease in the frequency, amplitude, and regularity of ultradian pulses. Whether these changes in insulin pulsatility contribute directly to the age-related changes in carbohydrate metabolism will require further clinical studies.     

Effect of ageing and diabetes on glucose-dependent insulinotropic polypeptide and dipeptidyl peptidase IV responses to oral glucose.

AIMS: Glucose-dependent insulinotropic polypeptide (GIP) acts on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). GIP is rapidly inactivated in vivo by the enzyme dipeptidyl dipeptidase IV (DPP-IV). The current studies were designed to examine the effect of ageing, obesity and diabetes on GIP and DPP-IV responses to oral glucose. METHODS: Healthy controls (nine middle-aged, age 42 +/- 2 years, body mass index (BMI) 33 +/- 1 kg/m2; nine elderly, age 71 +/- 1 years, BMI 30 +/- 1 kg/m2) and patients with Type 2 diabetes (12 middle-aged, age 44 +/- 2 years, BMI 34 +/- 2 kg/m2; 19 elderly, age 74 +/- 1 years, BMI 31 +/- 1 kg/m2) underwent a 3-h oral glucose tolerance test (OGTT) (glucose dose 40 g/m2). RESULTS: Insulin responses were similar in elderly controls and patients with diabetes, but were lower in middle-aged patients with diabetes than in controls (308 +/- 65 vs. 640 +/- 109 pM, P < 0.05). GIP responses were similar in controls and patients with diabetes in each age group, but were higher in elderly controls (middle-aged 45 +/- 13; elderly 112 +/- 13 pM, P < 0.01) and patients with diabetes (middle-aged 55 +/- 10; elderly 99 +/- 10 pM, P < 0.01). DPP-IV levels were lower in patients with diabetes in both middle-aged (control 0.241 +/- 0.015; diabetes 0.179 +/- 0.017 delta OD/20 min, P < 0.05) and elderly groups (control 0.223 +/- 0.019; diabetes 0.173 +/- 0.010 delta OD/20 min, P < 0.05). CONCLUSIONS: It was concluded that ageing in obese subjects is associated with enhanced GIP responses to oral glucose. In addition, DPP-IV activity is reduced in middle-aged and elderly obese patients with diabetes.     

Repaglinide treatment amplifies first-phase insulin secretion and high-frequency pulsatile insulin release in Type 2 diabetes.

AIMS/HYPOTHESIS: First-phase insulin release and coordinated insulin pulsatility are disturbed in Type 2 diabetes. The present study was undertaken to explore a possible influence of the oral prandial glucose regulator, repaglinide, on first-phase insulin secretion and high-frequency insulin pulsatility in Type 2 diabetes. METHODS: We examined 10 patients with Type 2 diabetes in a double-blind placebo-controlled, cross-over design. The participants were treated for 6 weeks with either repaglinide [2-9 mg/day (average 5.9 mg)] or placebo in random order. At the end of each treatment period, first-phase insulin secretion was measured. Entrainment of insulin secretion was assessed utilizing 1-min glucose bolus exposure (6 mg/kg body weight every 10 min) for 60 min during (A) baseline conditions, i.e. 12 h after the last repaglinide/placebo administration, and (B) 30 min after an oral dose of 0.5 mg repaglinide/placebo with subsequent application of time-series analyses. RESULTS: Postprandial (2-h) blood glucose was significantly reduced by repaglinide after 5 weeks of treatment (P < 0.001). The fall in HbA(1c) did not reach statistical significance (P = 0.07). AUC(ins,0-12 min) during the first-phase insulin secretion test was enhanced (P < 0.05). In addition, glucose entrained insulin secretory burst mass and amplitude increased markedly (burst mass: repaglinide, 44.4 +/- 6.0 pmol/l/pulse vs. placebo, 31.4 +/- 3.3 pmol/l/pulse, P < 0.05; burst amplitude: repaglinide, 17.7 +/- 2.4 pmol/l/min vs. placebo, 12.6 +/- 1.3 pmol/l/min, P < 0.05) while basal insulin (non-pulsatile) secretion was unaltered. After acute repaglinide exposure (0.5 mg) basal insulin secretion increased significantly (P < 0.05). Neither acute nor chronic repaglinide administration influenced frequency or regularity of insulin pulses during entrainment. CONCLUSION/INTERPRETATION: Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while regularity of the insulin release process was unaltered.     

Glucagon-like peptide-1 (7-37) augments insulin-mediated glucose uptake in elderly patients with diabetes.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose-induced insulin secretion in patients with type 2 diabetes. It has also been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs because this hormone enhances insulin-mediated glucose disposal. However, interpretations of the studies have been controversial. This study determines the effect of GLP-1 on insulin-mediated glucose disposal in elderly patients with type 2 diabetes. METHODS: Studies were conducted on 8 elderly patients with type 2 diabetes (age range, 76 +/- 1 years; body mass index, 28 +/- 1 kg/m(2)). Each subject underwent two 180-minute euglycemic (insulin infusion rate, 40 mU/m(2)/min) insulin clamps in random order. Glucose production (Ra) and disposal (Rd) rates were measured using tritiated glucose methodology. In one study, glucose and insulin alone were infused. In the other study, a primed-continuous infusion of GLP-1 was administered at a final rate of 1.5 pmol x kg(-1) x min(-1) from 30 to 180 minutes. RESULTS: Glucose values were similar between the control and GLP-1 infusion studies. 120- to 180-minute insulin values appeared to be higher during the GLP-1 infusion study (control, 795 +/- 63 pmol/l; GLP-1, 1140 +/- 275 pmol/l; p = not significant [NS]). The higher insulin values were largely due to 2 subjects who had substantial insulin responses to GLP-1 despite euglycemia and hyperinsulinemia. The 120- to 180-minute insulin values were similar in the other 6 subjects (control, 746 +/- 35 pmol/l; GLP-1, 781 +/- 41 pmol/l; p = NS). Basal (control, 2.08 +/- 0.05 mg/kg/min; GLP-1, 2.13 +/- 0.04 mg/kg/min; p = NS) and 120- to 180-minute (control, 0.50 +/- 0.18 mg/kg/min; GLP-1, 0.45 +/- 0.14 mg/kg/min; p = NS) Ra was similar between studies. The 120- to 180-minute Rd values were higher during the GLP-1 infusion studies (control, 4.73 +/- 0.39 mg/kg/min; GLP-1, 5.52 +/- 0.43 mg/kg/min; p <.01). When the 2 subjects who had significant insulin responses to GLP-1 during the euglycemic clamp were excluded, the 120- to 180-minute Rd values were still higher in the GLP-1 infusion study (control, 5.22 +/- 0.32 mg/kg/min; GLP-1, 6.05 +/- 0.37 mg/kg/min; p <.05). CONCLUSIONS: We conclude that GLP-1 may enhance insulin sensitivity in elderly patients with diabetes.     

Effect of aging and diabetes on the enteroinsular axis

BACKGROUND: The current studies were designed to examine the effect of aging and diabetes on the enteroinsular axis. METHODS: Healthy young control subjects (n = 10 young; age 23 +/- 1 years; body mass index [BMI] 24 +/- 1 kg/m(2)), healthy elderly subjects (n = 10; age 80 +/- 2 years; BMI 26 +/- 1 kg/m(2)), and elderly patients with type 2 diabetes (n = 10; age 76 +/- 2 years; BMI 26 +/- 2 kg/m(2)) underwent a 3-hour oral glucose tolerance test (glucose dose 40 gm/m(2)). RESULTS: Insulin responses were not different between young controls and elderly patients with diabetes but were significantly lower in elderly patients with diabetes and young controls than in elderly controls (young control: 178 +/- 27 pM; elderly control: 355 +/- 57 pM; elderly diabetes: 177 +/- 30 pM; p <.05 elderly control vs young control and elderly diabetes). Total glucagon-like peptide 1 (GLP-1) responses were not significantly different between young and elderly controls and patients with diabetes (young control: 15 +/- 2 pM; old control: 8 +/- 2 pM; elderly diabetes: 12 +/- 3 pM; p = ns). Active GLP-1 responses were also not different between young and elderly controls and patients with diabetes (young control: 5 +/- 1 pM; old control: 6 +/- 1 pM; elderly diabetes: 7 +/- 1 pM; p = ns). However, the difference between total and active GLP levels was significantly greater in the young controls (young control: 10 +/- 2 pM; old control: 2 +/- 2 pM; elderly diabetes: 4 +/- 2 pM; p <.05, young vs elderly). Glucose-dependent insulinotropic polypeptide responses were not different between young and elderly controls and between elderly controls and patients with diabetes but were significantly higher in elderly patients with diabetes than in young controls (young control: 97 +/- 12 pM; elderly control: 121 +/- 16 pM; elderly diabetes: 173 +/- 27 pM; p <.05, young vs elderly diabetes). Glucagon responses were reduced in elderly controls but were similar in young controls and elderly patients with diabetes (young control: 15 +/- 1 pM; elderly control: 9 +/- 1 pM; elderly diabetes: 16 +/- 1 pM; p <.01 elderly control vs young control and elderly diabetes). Dipeptidyl peptidase IV levels were lower in both elderly controls and patients with diabetes when compared with young controls (young control: 0.17 +/- 0.01; elderly control: 0.15 +/- 0.01; elderly diabetes: 0.15 +/- 0.01 DeltaOD/20 minutes; p <.05, elderly vs young). CONCLUSIONS: We conclude that normal aging and diabetes are associated with multiple changes in the enteroinsular axis.     

11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus

Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 +/- 13 yr; body mass index (BMI), 31.1 +/- 7.5 kg/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)).Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-HSD1 activity could not be explained by circulating levels of adipocytokines.Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.     

Peptide YY is secreted after oral glucose administration in a gender-specific manner

CONTEXT: Previous studies with small numbers of subjects showed a negative correlation between plasma peptide YY (PYY) levels and obesity. If correct, this would imply that low PYY levels might be involved in the pathogenesis of obesity. OBJECTIVE: Our objective was to investigate whether plasma PYY levels were correlated with sex and body mass index (BMI). DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of 151 normal volunteers (19-90 yr of age) in the Baltimore Longitudinal Study of Aging. INTERVENTIONS: All subjects had an oral glucose tolerance test (75 g) performed. MAIN OUTCOME MEASURES: Immunostaining of human duodenum, BMI, hemoglobin A1c, plasma glucose, insulin, PYY, glucagon like peptide-1 (GLP-1), ghrelin, and leptin were the main outcome measures. RESULTS: PYY and GLP-1 colocalized in the same cells in human duodenum. Both hormones reached peak plasma levels by 20 min and had similar secretory patterns. The incremental increases in PYY and GLP-1 during that first 20 min were significantly correlated (r2 = 0.388; P < 0.0001). The areas under the curve from 0-120 min for PYY and GLP-1 were similar in both obese and lean participants. Female participants across the range of BMI had significantly higher PYY area under the curve (17,464 +/- 1,240 vs. 14,120 +/- 806 pmol/liter x min, female vs. male; P < 0.05) compared with male participants. CONCLUSIONS: Our findings show that PYY and GLP-1 are colocalized and cosecreted from L cells and that total secretion of PYY is higher in females than in males, but fasting PYY levels and PYY secretion in response to oral glucose were not in any way correlated with BMI.     

The insulin gene variable number of tandem repeat: associations and interactions with childhood body fat mass and insulin secretion in normal children

CONTEXT: Polymorphism at the insulin gene (INS) variable number of tandem repeat (VNTR) shows variable associations with childhood body mass index (BMI) in different populations. OBJECTIVE: The objective of this study was to observe INS VNTR associations with body composition and insulin secretion in children. DESIGN: The study was designed as a prospective birth cohort study. PARTICIPANTS: A total of 947 children genotyped for the INS VNTR participated. MAIN OUTCOME MEASURES: Main outcome measures were whole body dual x-ray emission absorptiometry at 9 yr to estimate height-corrected fat mass index (FMI), truncal FMI, and fat-free mass, and insulin secretion after oral glucose at 8 yr. RESULTS: Homozygous III/III children had higher BMI (P = 0.020), FMI (P = 0.015), and truncal FMI (P = 0.022) at 9 yr than class I bearers, but no difference in fat-free mass (P = 0.23). Gain in weight sd score between birth and 3 yr was associated positively with BMI, FMI, and truncal FMI in class I bearers, but not in III/III children (p-interaction with genotype = 0.009-0.066). INS VNTR genotype was not associated overall with insulin secretion at 8 yr (P = 0.64), but class I bearers showed a stronger positive correlation between insulin secretion and BMI at 8 yr (regression coefficient +/- se, 0.26 +/- 0.05; P < 0.0001) than III/III children (-0.10 +/- 0.07; P = 0.48) (p-interaction = 0.003). CONCLUSION: We clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population relates to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. This genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity.     

Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.     

Effect of glucagon-like peptide-1 (7-37) on beta-cell function after islet transplantation in type 1 diabetes

Islet transplantation can improve glycemic control in patients with type 1 diabetes and reduce or eliminate the need for insulin. Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose induced insulin secretion, and has a trophic effect on beta-cells. We evaluated the effect of GLP-1 on insulin secretion after islet transplantation. Patients underwent hyperglycemic glucose clamp studies 1 month after their last transplant. GLP-1 was infused during the second hour of the hyperglycemic clamp. Results were compared to normal control subjects and patients with type 2 diabetes who underwent an identical hyperglycemic clamp. First phase insulin release was absent in patients, while second phase insulin was not significantly reduced (control: 118+/-29 pM; type 2 diabetes: 68+/-20 pM; transplant: 99+/-18 pM, p=ns for all). GLP-1 had a significant incretin effect on transplanted islets but the response was less than controls (control: 2108+/-344 pM; type 2 diabetes: 929+/-331 pM; transplant: 329+/-112 pM, p<0.0001 control versus transplant). Islet transplant patients had no evidence of resistance to insulin mediated glucose disposal. We conclude that transplanted islets retain the ability to respond to GLP-1.     

Effects of weight loss in obese subjects with normal fasting plasma glucose or impaired glucose tolerance on insulin release and insulin resistance according to a minimal model analysis

We investigated effects of weight loss from diet and exercise regimen in obese subjects with normal fasting plasma glucose or impaired glucose tolerance (IGT) on insulin release capacity and insulin sensitivity. Eight subjects were recruited among visceral obesity patients (4 men, 4 women; age range, 24 to 57 years; body mass index [BMI], 32.8 to 60.3 kg/m(2)). All were admitted to Chiba University Hospital for 2 weeks, were treated with a tapering 5,023 to 2,930 kJ diet, and were given exercise equivalent to 628 kJ/d. For assessments, we used a combination of C-peptide secretion rate determination and minimal model analysis as previously reported. BMI and visceral fat area (V) significantly decreased (BMI on initiation v after intervention, 43.0 +/- 3.2 v 40.3 +/- 3.1 kg/m(2), P <.05; V, 224 +/- 22 v 188 +/- 22 cm(2); P <.05). Fasting immunoreactive insulin (F-IRI) and leptin concentrations decreased significantly. Capacity for insulin release in response to glucose increased in all subjects (first-phase insulin secretion [CS1], 4.66 +/- 4.05 v 6.81 +/- 4.57 ng/mL/5 min, P <.05), but the insulin sensitivity index (S(i)) did not change significantly. These data suggest that weight reduction early in development of type 2 diabetes can oppose progression of diabetes by improving capacity for insulin release.     

Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients: restoration by rosiglitazone treatment

CONTEXT: The mitochondrial uncoupling protein-3 (UCP3) has been implicated in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Recent evidence points toward mitochondrial aberrations as a major contributor to the development of insulin resistance and diabetes, and UCP3 is reduced in diabetes. OBJECTIVE: We compared skeletal muscle UCP3 protein levels in prediabetic subjects [i.e. impaired glucose tolerance (IGT)], diabetic patients, and healthy controls and examined whether rosiglitazone treatment was able to restore UCP3. PATIENTS, DESIGN, INTERVENTION: Ten middle-aged obese men with type 2 diabetes mellitus [age, 61.4 +/- 3.1 yr; body mass index (BMI), 29.8 +/- 2.9 kg/m(2)], nine IGT subjects (age, 59.0 +/- 6.6 yr; BMI, 29.7 +/- 3.0 kg/m(2)), and 10 age- and BMI-matched healthy controls (age, 57.3 +/- 7.4 yr; BMI, 30.1 +/- 3.9 kg/m(2)) participated in this study. After baseline comparisons, diabetic patients received rosiglitazone (2 x 4 mg/d) for 8 wk. MAIN OUTCOME MEASURES: Muscle biopsies were sampled to determine UCP3 and mitochondrial protein (complex I-V) content. RESULTS: UCP3 protein content was significantly lower in prediabetic IGT subjects and in diabetic patients compared with healthy controls (39.0 +/- 28.5, 47.2 +/- 24.7, and 72.0 +/- 23.7 arbitrary units, respectively; P < 0.05), whereas the levels of the mitochondrial protein complex I-V were similar between groups. Rosiglitazone treatment for 8 wk significantly increased insulin sensitivity and muscle UCP3 content (from 53.2 +/- 29.9 to 66.3 +/- 30.9 arbitrary units; P < 0.05). CONCLUSION: We show that UCP3 protein content is reduced in prediabetic subjects and type 2 diabetic patients. Eight weeks of rosiglitazone treatment restores skeletal muscle UCP3 protein in diabetic patients.     

Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes

OBJECTIVE: To establish the antidiabetogenic effect of glucagon-like peptide-1 (GLP-1) when differently administered relative to meal intake in subjects with type 2 diabetes. DESIGN: The study was a placebo-controlled comparison with random assignment to treatment sequence. A 3-h stepwise infusion of GLP-1 (17 nmol) was started either at the onset of a standard meal (550 kCal) (A) or at 30 min (B) or 60 min (C) after the start of the meal. SETTING: The study was conducted at a university hospital. SUBJECTS: Eight patients with type 2 diabetes (four women and four men), age 62 +/- 3.9 years (range 47-74 years), weight 79.8 +/- 5.4 kg (range 62-104 kg), BMI 26.2 +/- 1.3 kg m(-2) (range 21-31 kg m(-2)), diabetes duration 10.5 +/- 2.0 years (range 3-19 years) and HbA1c levels 6.1 +/- 0.3% (range 4.7-7.7%) participated in the study. All patients were treated with oral sulphonylureas. RESULTS: Glucagon-like peptide-1 significantly lowered postprandial glycaemia by a similar degree in all three situations versus the control meal (P < 0.05). Postprandial insulin levels were not different in the four experimental series, whereas the postprandial glucagon levels were significantly lowered by GLP-1 in (A) and (B) (P < 0.03) but not in (C). Gastric emptying, as determined by the paracetamol test, was retarded by GLP-1 only in (A) (P < 0.01), but not affected in (B) or (C). CONCLUSIONS: GLP-1 reduced postprandial hyperglycaemia in subjects with type 2 diabetes regardless of administration at the onset of meal intake or at 30 or 60 min after start of meal intake, although the mechanism of the antidiabetogenic action of GLP-1 depended on administration versus meal intake. Thus, when administered at the start of a meal, GLP-1 was antidiabetogenic mainly through retarding gastric emptying, whereas when given at 30 or 60 min after meal ingestion, changes in islet hormone secretion seem to be predominant.     

Beta-cell function evaluated by HOMA as a predictor of secondary sulphonylurea failure in Type 2 diabetes.

BACKGROUND AND AIMS: Secondary failure to oral hypoglycaemic agents, a common evolution of long-standing Type 2 diabetes, is usually assessed by non-standardized indices requiring fine clinical assessment, including hyperglycaemia resistant to maximum doses of sulphonylureas despite appropriate diet and follow-up. The goal of this study was to evaluate if HOMA, a modelized plasma insulin/glucose ratio allowing simple evaluation of residual insulin secretion and sensitivity, is a better predictor of the insulin requiring stage than clinical indices. MATERIALS AND METHODS: HOMA was measured in 84 Type 2 diabetic patients aged 58 +/- SD 6 years, with diabetes duration 11 +/- 4 years, hospitalized because of hyperglycaemia resistant to maximal doses of sulphonylureas (e.g. glibenclamide > or = 15 mg/day), with no apparent external reason for hyperglycaemia. Despite reinforced appropriate diet recommendations, 62 of these patients remained hyperglycaemic (insulin-requiring group). RESULTS: Age, duration of diabetes, body mass index (BMI) and HOMA value for insulin sensitivity (71 +/- 6% vs. 76 +/- 7%, normal values 59-161%) were comparable in the two groups. HbA(1c) was higher (10.0 +/- 0.2% vs. 8.3 +/- 0.3%, P < 0.001) and HOMA insulin secretion values lower (25 +/- 2% vs. 43 +/- 6%, normal values 70-150%, P < 0.01) in the insulin-requiring group. Of the following potential predictors: HbA(1c) > 8%, duration of diabetes > or = 10 years, HbA(1c) combined with diabetes duration, insulin sensitivity < or = 40%, insulin secretion < or = 20%, the latter showed the best positive predictivity (86% patients with low insulin secretion were insulin-requiring). CONCLUSIONS: (i) HOMA is a simple and good predictor of the insulin-requiring stage in Type 2 diabetes mellitus; (ii) this stage of diabetes is characterized by a further decline of insulin secretion rather than of insulin sensitivity. Diabet. Med. 18, 584-588 (2001)     

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.     

Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval--a General Clinical Research Center study

Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21-34 yr) and 8 older (aged 62-72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (+/- SEM) serum PRL concentration was significantly reduced at 4.3 +/- 0.78 microg/L in older men compared with 9.5 +/- 1.2 microg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = +0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 +/- 0.23 (older) vs. 3.9 +/- 0.57 microg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 +/- 0.00027 (older) vs. 0.00065 +/- 0.0002 microg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 +/- 5.3% in young and 99 +/- 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging. Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic) input to lactotrophs in older men. Given the multiple roles of PRL reported in experimental animals (e.g. on the one hand to support immune function and adrenal androgen biosynthesis and on the other hand to activate intraprostatic growth factors), we suggest that the nocturnal relative hypoprolactinemia observed in healthy aging men may have both adaptive and maladaptive clinical implications to target tissues.     

The conscious Göttingen minipig as a model for studying rapid pulsatile insulin secretion in vivo

AIMS/HYPOTHESIS: Pulsatile secretion is important for insulin action and suitable animal models are important tools for examining the role of impaired pulsatile insulin secretion as a possible link between beta-cell mass, function and morphology and insulin resistance. This study examines the vascular sampling site, insulin kinetics, pulsatility and the response to glucose pulse entrainment to evaluate the G?ttingen minipig as a model for studying pulsatile insulin secretion. METHODS: Basal and glucose entrained insulin secretion was examined in normal minipigs and evaluated by autocorrelation, cross correlation and deconvolution. RESULTS: Cross correlation showed a relation between oscillations in insulin concentrations in the portal and jugular vein in anaesthetised animals ( p<0.001 in all animals), confirming the usefulness of jugular vein sampling for pulse detection. Jugular vein sampling in conscious animals showed obvious oscillations allowing estimates of burst shape and insulin kinetics. Glucose entrainment improved the pulsatile pattern (autocorrelation: 0.555+/-0.148 entrained vs 0.350+/-0.197 basal, p=0.054). Deconvolution analysis resolved almost all insulin release as secretory bursts (69+/-20 basal vs 99.5+/-1.2% entrained, p<0.01) with a pulse interval (min) of 6.6+/-2.2 (basal) and 9.4+/-1.5 (entrained) ( p<0.05) and a pulse mass (pmol/l per pulse) which was higher after entrainment (228+/-117 vs 41.2+/-18.6 basal, p<0.001). CONCLUSION/INTERPRETATION: The ability to fit kinetic parameters directly by deconvolution of peripheral endogenous insulin concentration time series in combination with the suitability of jugular vein sampling, rapid kinetics and entrainability makes the G?ttingen minipig ideal for mechanistic studies of insulin pulsatility and its effects on insulin action.     

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

Aims/hypothesis. The enteric incretin hormone, glucagon-like peptide-1 (GLP-1), is a potent insulin secretagogue in healthy humans and patients with Type II (non-insulin-dependent) diabetes mellitus. In this study we assessed the impact of short-term GLP-1 infusion on pulsatile insulin secretion in Type II diabetic patients. Methods. Type II diabetic patients (n = 8) were studied in a randomised cross-over design. Plasma insulin concentration time series were obtained during basal conditions and during infusion with saline or GLP-1 (1.2 pmol/l · kg^–1· min^–1) on 2 separate days. Plasma glucose was clamped at the initial concentration by a variable glucose infusion. Serum insulin concentration time series were evaluated by deconvolution analysis, autocorrelation analysis, spectral analysis and approximate entropy. Results. Serum insulin concentrations increased by approximately 100 % during GLP-1 infusion. Pulsatile insulin secretion was increased as measured by secretory burst mass (19.3 ± 3.8 vs 53.0 ± 10.7 pmol/l/pulse, p = 0.02) and secretory burst amplitude (7.7 ± 1.5 vs 21.1 ± 4.3 pmol/l/min, p = 0.02). A similar increase in basal insulin secretion was observed (3.6 ± 0.9 vs 10.2 ± 2.2 pmol/l/min, p = 0.004) with no changes in the fraction of insulin delivered in pulses (0.50 ± 0.06 vs 0.49 ± 0.02, p = 0.84). Regularity of secretion was unchanged as measured by spectral analysis (normalised spectral power: 5.9 ± 0.6 vs 6.3 ± 0.8, p = 0.86), autocorrelation analysis (autocorrelation coefficient: 0.19 ± 0.04 vs 0.18 ± 0.05, p = 0.66) and the approximate entropy statistic (1.48 ± 0.02 vs 1.51 ± 0.02, p = 0.86). Conclusion/interpretation. Short-term stimulation with GLP-1 jointly increases pulsatile and basal insulin secretion, maintaining but not improving system regularity in Type II diabetic patients. [Diabetologia (2000) 43: 583–588] Received: 11 November 1999 and in revised form: 13 December 1999     

Appetite regulatory hormone responses to various dietary proteins differ by body mass index status despite similar reductions in ad libitum energy intake

CONTEXT: Although dietary protein produces higher acute satiety relative to carbohydrate, the influence of protein source and body mass index (BMI) has not been clearly described. OBJECTIVE: The objective of the study was to assess postprandial responses to different protein sources, compared with glucose, in males with normal and high BMI. DESIGN: This was a randomized, crossover study of four preloads followed by blood sampling (+15, 30, 45, 60, 90, 120, 180 min) and buffet meal. SETTING: The study was conducted at an outpatient clinic. PARTICIPANTS: The study population included 72 men, with a BMI range 20.6-39.9 kg/m(2). INTERVENTIONS: Interventions consisted of liquid preloads (1.1 MJ, 450 ml) containing 50 g whey, soy, gluten, or glucose. MAIN OUTCOME MEASURES: Fasting and postprandial plasma glucose, insulin, ghrelin, glucagon-like peptide-1 (GLP-1) and cholecystokinin (n = 38), ad libitum energy intake, and appetite ratings were measured. RESULTS: Energy intake was 10% lower after all protein preloads, compared with the glucose treatment (P < 0.05), independent of BMI status and protein type. All protein loads prolonged the postprandial suppression of ghrelin (P < 0.01) and elevation of GLP-1 (P < 0.01) and cholecystokinin (P < 0.05). Fasting GLP-1 concentrations [overweight, 17.5 +/- 1.3; lean, 14.7 +/- 0.1 pg/ml (5.2 +/- 0.4 and 4.4 +/- 0.1 pmol/liter, respectively); P < 0.001] and postprandial responses (P = 0.038) were higher in overweight subjects. CONCLUSIONS: Whey, soy, and gluten similarly tend to reduce ad libitum food intake 3 h later in lean and overweight males relative to glucose. Postprandial ghrelin, GLP-1, insulin, and cholecystokinin may contribute to this higher satiety after protein consumption. GLP-1 concentrations are increased in overweight subjects, which may affect satiety responses in this group.