Initial Insulin Response Research Articles

012 Overnight light exposure acutely increases heart rate during sleep and decreases insulin sensitivity the following day

Abstract Introduction Prior reports indicate that exposure to light at night negatively impacts sleep quality, autonomic and metabolic function, but the interaction between these physiologically interconnected systems is not fully elucidated. We examined the acute effects of nighttime light exposure on sleep macro and microarchitecture, heart rate (HR) and response to oral glucose tolerance test (OGTT), and the relationship between these measures. Methods Twenty healthy adults (18 - 40 years) were randomized into Light or Dark groups and run in parallel for a three-day and two-night laboratory stay. The Light group (n=10) slept in the dark (< 3 lux) on Night 1 and slept with overhead room lights on (100 lux) on Night 2, while the Dark group (n=10) slept in the dark (< 3 lux) on both Nights 1 and 2. Overnight polysomnography (PSG) was used to assess sleep macro and microstructure (slow wave activity: SWA: 0.5–4 Hz, and slow oscillatory (SO) activity: 0.5–1 Hz), and beat-to-beat measurement of HR. A two-hour OGTT was completed each morning. The between groups change in PSG-derived measures and metabolic parameters from Night/Day 2 to Night/Day 1, was calculated. Results While a greater percentage of time was spent in stage 2 (p= 0.003) and a smaller percentage of time was spent in stage 3 (p= 0.04), there were no between group differences in SWA and SO activity. Time series analysis of HR changes across the night from Night 1 to Night 2 showed higher HR in the Light vs the Dark group (p< 0.001). The change from Day 1 to Day 2 of the initial insulin response (60-min. area under the curve, AUC) showed a higher insulin response in the Light vs the Dark group (p= 0.029). The change in HR was positively correlated with the change in the 60-min. AUC of insulin (R= 0.46, p= 0.049). Conclusion A single overnight light exposure acutely increases heart rate during sleep and decreases insulin sensitivity the following day and these responses appear to be associated, suggesting that elevated autonomic activity in response to light at night impacts next day metabolic responses. Support (if any) Center for Circadian and Sleep Medicine, UL1TR001422

A Hydrothermally Processed Maize Starch and Its Effects on Blood Glucose Levels During High-Intensity Interval Exercise.

Hetrick, MM, Naquin, MR, Gillan, WW, Williams, BM, and Kraemer, RR. A hydrothermally processed maize starch and its effects on blood glucose levels during high-intensity interval exercise. J Strength Cond Res 32(1): 3-12, 2018-A hydrothermally processed maize starch (HPMS) has been shown to blunt initial blood glucose and insulin response during endurance activity at 70% maximal oxygen uptake (V[Combining Dot Above]O2max). High-intensity interval training (HIIT) is a form of exercise that has many health benefits although it is only performed for short periods of time with interspersed rest periods. The purpose of this study was to compare the blood glucose and associated metabolic stress responses to a sprint interval cycling (SIC) exercise protocol (a form of HIIT) with and without an HPMS in a healthy population. Fourteen subjects completed a total of 4 sessions: a preliminary session, an SIC session with HPMS, an SIC session without HPMS, and a control session in which only HPMS was ingested. Blood glucose, blood lactate, respiratory exchange ratio, oxygen consumption, and rating of perceived exertion responses were recorded during the sessions. There was a significant and progressive rise in blood glucose levels during each of the cycle sprints of both exercise sessions, but not a significant difference between treatment or nontreatment SIC sessions. This is the first study to determine blood glucose responses to SIC after each sprint interval and to report that ingestion of HPMS does not affect glucose responses to SIC. The findings provide some preliminary evidence suggesting subjects at risk for glucose excursions could use SIC to improve health through monitoring blood glucose concentrations during SIC and if necessary, modifying number, intensity, and duration of sprints completed.

Abstract 017: Spironolactone Improves Insulin Secretion In Metabolic Syndrome Subjects

Renin-angiotensin-aldosterone system blockade reduces the incidence of type 2 diabetes in clinical trials. We previously demonstrated that aldosterone impairs insulin secretion via a direct beta-cell effect in mice. To test the hypothesis that aldosterone and the mineralocorticoid receptor contribute to impaired insulin secretion in humans, we enrolled subjects with metabolic syndrome treated with hydrochlorothiazide (HCTZ) 12.5 mg daily for 4 weeks (baseline) followed by either Spironolactone 25 mg daily (SPL, n=16) versus Aliskiren 150 mg daily (ALI, n=19) for 4 weeks. We assessed insulin secretion and sensitivity using hyperglycemic clamps during sodium controlled diet (160 mmol Na). During HCTZ alone, plasma aldosterone correlated inversely with the initial insulin response and disposition index (Figure A), but not with insulin sensitivity index. Plasma aldosterone decreased during aliskiren (-1.5±0.78 ng/dL) and increased during spironolactone treatment (+4.0±0.8 ng/dL; p<0.001 between treatment). Blood pressure, serum potassium, and insulin sensitivity index were unchanged. The acute insulin response increased compared to baseline during SPL compared to ALI (+11.6±7.9 vs -10.7±7.7 μU/mL; p=0.048), whereas insulin sensitivity index was unchanged. We conclude that aldosterone is inversely associated with the initial phase insulin secretory response, the earliest detectable change in impaired glucose tolerance. Treatment with spironolactone could improve glucose homeostasis by restoring insulin secretion in subjects with metabolic syndrome.

Prepartum dietary energy source fed to beef cows: II. Effects on progeny postnatal growth, glucose tolerance, and carcass composition1

Mature Angus-cross beef cows (n = 228) were used to evaluate effects of prepartum dietary energy source on postnatal growth and carcass composition of progeny in a 2-yr study. Starting at approximately 160 d of gestation, cows were fed diets consisting of 1 of 3 primary energy sources: grass hay (HY), corn (CN), or dried corn distillers grains with solubles (DG). The CN and DG diets were limit-fed to achieve similar energy intakes as cows fed HY. Following parturition, cows were fed a common diet and managed as a single group. Calves were weaned at an average of 185 ± 6 d of age and backgrounded for 28 d. A subset of progeny (n = 134) was individually fed a common finishing diet until slaughter, when each calf reached 1.2 ± 0.05 cm of backfat. A glucose tolerance test (GTT) was conducted in year 2 on 4 calves/treatment after 41 and 111 d on the finishing diet (DOF). Calf birth weights were greater (P = 0.002) in calves from cows fed CN and DG than calves from cows fed HY, and weaning BW (P = 0.08) was less for calves from cows fed HY vs. CN. Receiving BW, final BW, and HCW did not differ (P ≥ 0.16) among treatments. No difference (P ≥ 0.28) in ADG, morbidity, and mortality from birth to slaughter was observed among treatments. In response to a GTT, increased DOF resulted in greater (P ≤ 0.005) fasting insulin, faster glucose disappearance rate, and greater insulin:glucose area under the curve ratio. Glucose disappearance rate was greater (P = 0.01) in calves from cows fed CN than in calves from cows fed HY or DG. A greater initial insulin response (P = 0.005) was observed in calves from cows fed CN or DG than in calves from cows fed HY. Carcass traits used to measure yield grade did not differ (P ≥ 0.19) among treatments. Calves from dams fed CN had the lowest marbling score (P = 0.03) and intramuscular fat content (P = 0.07). These results indicate that prepartum maternal dietary energy source can alter fetal adipose tissue development and insulin sensitivity resulting in long-term effects on progeny's intramuscular fat deposition. Moreover, present findings suggest that increasing the number of days on a corn-based finishing diet increases insulin resistance in beef cattle.

Winter-feeding systems for gestating sheep II. Effects on feedlot performance, glucose tolerance, and carcass composition of lamb progeny1

Mature pregnant crossbred ewes (n = 90) were used in a randomized complete block design experiment and were assigned to 1 of 3 winter-feeding systems differing in primary feed source: haylage (HL), limit-fed corn (CN), or limit-fed dried distillers grains (DDGS). Effects of these winter-feeding strategies on postweaning progeny performance were determined. Lamb progeny (n = 96) were weaned at 61 ± 4 d of age and fed a common high-concentrate diet. Lambs were assigned to feedlot pen (n = 18) based on dam mid-gestation pen. Growth rate, DMI, and ADG were determined for the first 40 d of the finishing period. At 96 ± 4 d of age, 1 wether lamb was randomly selected from each pen (n = 18) for a glucose tolerance test. The experiment was terminated, and lambs were slaughtered individually when they were determined to have achieved 0.6-cm 12th-rib fat thickness. After a 24-h chill, carcass data were collected and a 2.54-cm chop was removed from each lamb from the LM posterior to the 12th rib for ether extract analysis. Additional carcass measurements of bone, muscle, and fat from the shoulder, rack, loin, and leg were collected on 35 carcasses. At weaning, lamb BW was not different among treatments, whereas final BW tended to be greater (P = 0.09) for lambs from ewes fed DDGS and CN during gestation than from those fed HL. Overall lamb growth rate from birth to slaughter was not different among treatments. Lambs from ewes fed DDGS vs. CN or HL tended to have a greater initial insulin response (P = 0.09). Dressing percent was less (P = 0.04) in lambs from ewes fed DDGS, but no difference (P = 0.16) was detected in HCW among treatments. As expected, 12th rib fat thickness was similar among treatments, whereas LM area was largest to smallest (P = 0.05) in lambs from ewes fed CN, HL, and DDGS, respectively. Proportion of internal fat tended to be greatest to smallest (P = 0.06) in lambs from ewes fed DDGS, CN, and HL, respectively. Calculated boneless trimmed retail cuts percentage was less (P = 0.04) in lambs from ewes fed DDGS than CN or HL. Loin muscle weight as a percentage of wholesale cut tended (P = 0.10) to be greater in lambs from ewes fed CN and HL than DDGS, whereas other muscle, bone, and fat weights and proportions were similar (P > 0.24) among treatments. Prepartum diet during mid to late gestation of ewes altered postnatal fat and muscle deposition and may be associated with alterations in insulin sensitivity of progeny.

The incretin hormones GIP and GLP‐1 in diabetic rats: effects on insulin secretion and small bowel motility

Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L(-1)) or GLP-1 (10 nmol L(-1)) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1-400 pmol kg(-1) min(-1)) or GLP-1 (0.1-20 pmol kg(-1) min(-1)). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6-16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.

A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis

The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipid-derived signal essential for normal insulin secretion.

The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance

Background The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM). Objective and design To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance (NGT) (fasting plasma glucose (FPG): 5.5 (4.5–6.0) mM (mean (range); HbA 1c: 5.8 (5.4–6.3) %) and 8 patients with CP and secondary diabetes not requiring insulin (FPG: 7.1 (6.0–8.8) mM; HbA 1c: 7.0 (5.8–10.0) %) during three 15-mM hyperglycaemic clamps with continuous iv infusion of saline, glucagon-like peptide-1 (GLP-1) or GIP. Results The initial (0–20 min) insulin and C-peptide responses were enhanced significantly in both groups by GLP-1 and GIP, respectively, compared to saline ( P < 0.05). In both groups GLP-1 infusion resulted in significantly greater insulin and C-peptide responses from 20–120 min compared with saline infusion. During GIP infusion the late-phase insulin response (20–120 min) was 3.1 ± 1.0 fold greater than during saline infusion in the group of patients with CP and NGT ( P < 0.05), whereas there was no significant differences in patients with CP and DM. Conclusions The lack of GIP amplification of the late insulin response to iv glucose develops alongside the deterioration of glucose tolerance in patients with CP, suggesting that the same may be true for the loss of the GIP effect in patients with T2DM.

Comparison of Plasma Insulin Levels after a Mixed-Meal Challenge in Children with and without Intrauterine Exposure to Diabetes

The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring. We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 +/- 1.1 yr) or after (OPDM, n = 22, 9.5 +/- 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest. After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point. After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01). A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children.

Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1‐year trial results

To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy. Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study. There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain. No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.

Impaired circulating glucagon‐like peptide‐1 response to oral glucose in women with previous gestational diabetes

Women with previous gestational diabetes (pGDM) are at risk of developing Type 2 diabetes. Glucagon-like peptide-1 (GLP-1) potentiates the insulin response to oral glucose, and its secretion is diminished in Type 2 diabetes. The aim of the study was to see if decreased GLP-1 secretion might be an early abnormality in the progression to Type 2 diabetes and would therefore be diminished in women with pGDM. Eleven women with pGDM and previously documented normal glucose tolerance and 11 control women underwent a 75 g oral glucose tolerance test (OGTT). Circulating plasma glucose, insulin, nonesterified fatty acids (NEFA) and GLP-1 concentrations were sampled. One of the women with pGDM had impaired glucose tolerance and was excluded from the study. All other women had normal glucose tolerance. The women with pGDM had higher fasting glucose concentrations than controls (5.1; 4.9-5.3 vs. 4.8; 4.4-5.1 mmol/l, median; interquartile range, P = 0.04) and greater circulating glucose area under the curve (AUC) following the oral glucose load (930; 818-1015 vs. 668; 584-737 min x mmol/l, P = 0.0007). Fasting insulin concentrations and total insulin AUC were similar. The initial (0-30 min) insulin response was decreased in the pGDM women (AUC 3981; 2783-4795 vs. 6167; 5009-8145 min x pmol/l, P = 0.05). The initial (0-30 min) GLP-1 response was reduced in the pGDM women (AUC 816; 663-984 vs. 1163; 872-2024 min x pmol/l, P = 0.02). A reduced initial GLP-1 response to oral glucose may therefore be an early abnormality in the progression to Type 2 diabetes.

A comparison between Japanese-Americans living in Hawaii and Los Angeles and native Japanese: the impact of lifestyle westernization on diabetes mellitus

We have been conducting the Hawaii–Los Angeles–Hiroshima Study since 1970, mainly to determine the effects of environmental changes on various diseases by comparing Japanese-Americans with native Japanese subjects. Japanese-Americans living in Hawaii and Los Angeles are originated mainly from Hiroshima, Japan and are genetically identical with native Japanese. Through this study, we made several clear observations about Japanese-Americans. First, Japanese-Americans were highly exposed to a westernized lifestyle ; in other words, a relatively high fat and simple carbohydrate diet with low physical activity as compared to native Japanese. Second, the prevalence of type 2 diabetes among Japanese-Americans and death from ischemic heart disease among Japanese-American diabetic patients were higher. Third, the serum fasting insulin level as well as the insulin level after a glucose load, was higher among Japanese-Americans, even when the serum glucose levels were not statistically different as compared to native Japanese. Accordingly, Japanese-Americans were thought to have a high insulin resistance status. However, the initial insulin response after a glucose load was low, which was more similar to Japanese people than to Caucasians. Fourth, the total cholesterol and triglyceride levels were higher among Japanese-Americans. These results are supposed to be derived from the insulin resistant status by the westernization of lifestyle, as well as from the weakness of pancreatic β cell function that is supposed to be genetically regulated among Japanese. In conclusion, it appears that for genetically Japanese people, environmental factors are important for the development of metabolic diseases such as diabetes mellitus and cardiovascular disease.

Impaired insulin secretion in the Turner metabolic syndrome.

An increased prevalence of impaired glucose homeostasis (IGH) and diabetes mellitus is reported in monosomy X, or Turner syndrome (TS). To determine whether IGH is an intrinsic feature of this syndrome, independent of obesity or hypogonadism, we compared results of a standard oral glucose challenge in age- and body mass index-matched women with TS and with karyotypically normal premature ovarian failure (POF). Fasting glucose levels were normal in both groups, but glucose values after oral glucose challenge were higher in TS [2-h glucose, 135 +/- 36 mg/dl (7.5 +/- 2.0 mmol/liter) in TS and 97 +/- 18 mg/dl (5.4 +/- 1.0 mmol/liter) in POF; P < 0.0001]. Glucose-stimulated insulin secretion was lower in TS; e.g. the initial insulin response (DeltaI/DeltaG(30)) was decreased by 60% compared with POF (P < 0.0001). We also compared responses to a standard iv glucose tolerance test in women with TS and in age- and body mass index-matched normal women and found that the insulin area under the curve was 50% lower in women with TS (P = 0.003). Insulin sensitivity measured by the quantitative insulin sensitivity check index was higher in women with TS compared with both control groups. Thus, IGH is not secondary to obesity or hypogonadism in TS, but it is a distinct entity characterized by decreased insulin secretion, suggesting that haploinsufficiency for X-chromosome gene(s) impairs beta-cell function and predisposes to diabetes mellitus in TS.

Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice.

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells. GIPR-/- mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR-/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.

A Prospective Study of Health Check Examinees for the Development of Non‐insulin‐dependent Diabetes Mellitus: Relationship of the Incidence of Diabetes with the Initial Insulinogenic Index and Degree of Obesity

A total of 1788 non-diabetic subjects, screened by a general health check, had either glycosuria or marginal elevation of fasting blood glucose and/or HbA1c. They were followed by repeated 100 g oral glucose tolerance tests for up to 8 years. Their initial mean age was 52 years and the mean BMI was 23.2. Low insulin secretory response was defined when the insulinogenic index, a ratio of increment of plasma insulin to that of plasma glucose 30 min after oral glucose load, was lower than 0.5. Cumulative incidence of diabetes with fasting blood glucose (FBG) exceeding 120 mg dl-1 was significantly higher in impaired glucose tolerance (IGT) than in non-IGT, and in each of IGT and non-IGT groups, the incidence was significantly higher for low than normal insulin responders. The mean initial plasma insulin response in subjects who developed diabetes was significantly lower than in those who remained non-diabetic with the same category of glucose tolerance at baseline irrespective of the degree of glucose intolerance. The mean baseline BMI did not differ whether or not they developed diabetes, but a few cases who developed diabetes despite normal initial insulin response were much more obese. Fasting insulin levels did not correlate with FBG during the course of development of diabetes. We suggest that defective insulin secretion plays a predominant role in the non-obese subtype of NIDDM which includes the majority of Japanese patients, while both insulin resistance and insulin secretory defect are important in the obese subtype for the development of diabetes.

Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.

Masking of diabetic phenotype on a low-energy diet despite persistence of impaired insulin response

Type 2 diabetes has been postulated to be a “thrifty genotype” that aids fuel conservation; to investigate this hypothesis, type 2 diabetic and nondiabetic subjects, normal weight and obese, were studied after both 6 days on a 700-calorie diet and 6 days on a 2,800-calorie diet. On 2,800 calories per day, the median basal plasma glucose was raised in diabetics compared with nondiabetic subjects (median, 5.5 and 4.5 mmol/L, respectively; P = .003), but on the low-energy diet there was no difference (4.1 and 3.7 mmol/L, respectively; P > .05). Basal plasma insulin levels were similar in the diabetic and nondiabetic subjects and were twofold to threefold higher on the high- than low-energy diet in both diabetic (median, 7.8 and 3.1 mU/L on high- and low-energy diets, respectively; P = .007) and nondiabetic subjects (6.8 and 2.6 mU/L, respectively; P = .005). Similarly, the postprandial insulin concentrations increased to the same degree on the high- compared with the low-energy diet in diabetic (median postprandial increment, 14.9 and 3.4 mU/L; P = .005) and nondiabetic patients (9.5 and 3.0 mU/L; P = .005) and the β cells in type 2 diabetes appeared to modulate normally to different calorie intakes. On both diets, the diabetic subjects had an impaired first-phase insulin response to an intravenous glucose load compared with nondiabetic subjects (high-energy diet median first-phase increment, 4.3 and 21.2 mU/L in diabetic and nondiabetic subjects, P = .0007; low-energy diet, 4.0 and 20.4 mU/L, respectively, P = .003). The normal-weight diabetic subjects also had an impaired initial insulin response to meals on the high-energy diet (median increment at 60 minutes, 9 and 22 mU/L in diabetic and nondiabetic subjects, respectively; P < .05) without a significant difference on the low-energy diet (5 and 12 mU/L, respectively; P > .1). On the low-energy diet, the diabetic subjects had only marginal hyperglycemia, and the diabetic trait may not be sufficiently expressed to be harmful on a restricted diet. This may account for the persistence of a potentially harmful genetic disease during the evolution of man. Diabetic and nondiabetic subjects had a similar weight loss and a similar increase in plasma ketone bodies on the low-energy diet, and the diabetic subjects did not appear to have a “thrifty” response with fuel conservation on a low-energy diet.

The initial physiological responses to glucose ingestion in normal subjects are modified by a 3 d high-fat diet

The present study was designed to investigate whether 3 d of high-fat, low-carbohydrate diet (with normal daily energy intake) affected the metabolic, cardiovascular and thermic responses to an oral glucose load (1.5 g/kg body-weight). Eight normal weight, healthy subjects (five male) consumed diets containing approximately 65% by energy of carbohydrate (C) or fat (F), each for 3 d. Before and after glucose ingestion, continuous recordings of oxygen consumption and carbon dioxide production were made using indirect calorimetry, and metabolic rate (MR) and respiratory exchange ratio (RER) were calculated. Heart rate, blood pressure and limb blood flow were also measured. There was no significant change in baseline MR following the high-fat diet, but the fasting RER was reduced. The high-fat diet modified the responses to oral glucose, with a greater increase in MR (kJ/min; C + 0.38, F +0.76), and an enhanced plasma insulin response (mU/l; C + 51.5, F + 85.0). There were no differences between the two diets with respect to the baseline blood glucose levels or the changes after glucose ingestion. Heart rate, systolic and diastolic blood pressures and blood flow responses to the glucose load were similar after the two diets. There was no plasma catecholamine response to glucose ingestion. It can be concluded that a high-fat diet alters the initial thermic response and insulin response but does not alter the other physiological responses to glucose ingestion.

Effect of synthetic human glucose‐dependent insulinotropic polypeptide (hGIP) on the release of insulin in man

During an oral glucose tolerance test (oGTT) and an isoglycaemic intravenous glucose infusion, blood glucose and the responses of insulin and glucose-dependent insulinotropic polypeptide (GIP) were measured in six healthy volunteers. On a subsequent occasion a constant infusion of human synthetic GIP (2 pmol kg-1 min-1 for 30 min and 0.5 pmol kg-1 min-1 for another 30 min was given to each subject, again with a simultaneous infusion of glucose to maintain isoglycaemia to the oGTT. During the oGTT, plasma GIP concentrations rose from 92 +/- 18 pmol 1(-1) to 257 +/- 42 pmol 1(-1) 60 min after ingestion of glucose (mean +/- SEM). When glucose was administered intravenously plasma GIP levels did not rise significantly over basal. The infusion of hGIP mimicked the physiological plasma GIP response after oral glucose during the first 60 min of the study. Plasma insulin concentrations were significantly lower between 45 and 60 min than during the oGTT (438 +/- 67 vs. 200 +/- 48 pmol 1(-1); P less than 0.02; 465 +/- 96 vs. 207 +/- 48 pmol 1(-1); P less than 0.01). However, the total and incremental integrated insulin responses during the first 60 min of the study were, though lower, not significantly different from the oGTT experiment when glucose and hGIP were infused simultaneously. Thus, in the presence of mild physiological hyperglycaemia, human GIP is able to enhance the initial insulin response almost equivalently to the stimulus provided by oral glucose. Decreased insulin concentrations during porcine GIP infusions in previous experiments might be due to sequence differences between human and porcine GIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of four orally administered analogues of prostaglandin E1 and E2 on glucose tolerance and on the secretion of pancreatic and gastrointestinal hormones in man

Oral glucose tolerance tests (75 g, 300 ml) were performed in 12 healthy volunteers, with prior administration of placebo, misoprostol (400 micrograms), rioprostil (300 micrograms), enprostil (70 micrograms), or nocloprost (200 micrograms), in a double-blind, randomized manner. None of the drugs significantly affected glucose tolerance, although with misoprostal some volunteers displayed an impaired glucose tolerance. Nocloprost was without effect on gastric inhibitory polypeptide (GIP) and did not influence insulin or C-peptide concentrations. Misoprostol and rioprostil reduced integrated incremental responses of GIP by 57% (P less than or equal to 0.001) and 45% (P less than or equal to 0.01), respectively, and both gave rise to an initial (approximately 10 min) delay of insulin and C-peptide responses, without a significant overall reduction in integrated incremental responses. Enprostil almost totally inhibited the GIP response (by 94%; P less than or equal to 0.001), delayed initial insulin and C-peptide responses, but reduced the integrated incremental C-peptide response (which corresponds to the overall release of insulin) by only 14% (P less than or equal to 0.05). Enprostil more substantially reduced the integrated incremental response of insulin by 36% (P less than or equal to 0.01), and also reduced the ratio of insulin and C-peptide incremental responses (P less than or equal to 0.001). In conclusion, prostaglandin E analogues which caused a reduction in GIP responses, and thereby disrupting the enteroinsular axis to varying degrees, delayed the time-course of insulin secretion without a significant impact on glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)