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Purpose: Whey protein (WP) consumption prior to a meal curbs appetite and reduces postprandial glucose (PPG) through stimulating endogenous GLP-1 secretion and insulin. Methods: We assessed the metabolic effects of a concentrated WP, using a new micelle-technology (WPM), in people with type 2 diabetes (T2D) and overweight or obesity (NCT04639726). In a randomized-crossover design, participants performed two 240 min lunch meal (622 kcal) tests 7 ± 4 days apart. After an overnight fast and a standardized breakfast, 10 g (125 mL) WPM (40 kcal) or placebo (125 mL water, 0 kcal) was consumed 15 min ahead of the mixed-nutrient meal. Effects on PPG (primary endpoint), insulin, GLP-1, and branched-chain amino acids (BCAAs) were evaluated with frequent blood sampling. Changes in incremental areas under the concentration curve (iAUC) were compared using a mixed model. Results: Twenty-six individuals (14 females, mean ± SD age 62.0 ± 8.3 years, HbA1c 58 ± 12 mmol/mol/7.5 ± 1.1%, BMI 29.2 ± 4.8 kg/m2) completed both tests. WPM significantly reduced PPG iAUC0–2h by 22% (p = 0.028), and iAUC0–3h numerically by −18% (p = 0.090) vs. placebo. WPM also increased insulin iAUC0–1h by 61% (p < 0.001), and iAUC0–3h by 30% (p = 0.004), respectively. Total GLP-1 iAUC0–2h was enhanced by 66% (p < 0.001). Postprandial plasma BCAA patterns were characterized by a rapid increase and larger iAUC0–2h (all p < 0.001) after WPM. No adverse events were ascribed to consuming WPM. Conclusions: A 125 mL pre-meal drink containing just 10 g WPM before a mixed meal reduced PPG and increased insulin, GLP-1, and BCAAs. WPM may therefore serve as a metabolic modulator in people with T2D living with overweight or obesity. [ABSTRACT FROM AUTHOR]

Objectives: Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all‐cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported. Methods: Fasting levels of serum total adiponectin were measured cross‐sectionally in ≥40‐year‐old Kitavans (n = 102) and Swedish controls matched for age and sex (n = 108). Multivariable linear regression was used for the analysis of associations with total adiponectin when controlled for group, sex, smoking, hypertension and/or type 2 diabetes, age, and body mass index. Results: Total adiponectin was lower for Kitavans compared to Swedish controls (Median [Mdn] 4.6 μg/mL, range 1.0–206 μg/mL and Mdn 9.7 μg/mL, range 3.1–104 μg/mL, respectively, r =.64, p <.001). Lower total adiponectin was associated with Kitavan group, male sex (only in Swedish controls), smoking (only in Kitavans and Swedish controls combined), younger age (not in Swedish controls), higher BMI, lower total, low‐density lipoprotein, high‐density lipoprotein (HDL) (only in Kitavans and Swedish controls combined), and non‐HDL cholesterol, and higher anti‐PC IgG (only in Kitavans and Swedish controls combined). Conclusion: Total adiponectin in Kitavans was significantly lower than in Swedish controls. [ABSTRACT FROM AUTHOR]

To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P

ObjectiveThe metabolism of arachidonic acid (AA) has been shown to be altered in severe insulin resistance that is present in obese (fa/fa) Zucker rats. We examined the effects and mechanism of action of AA on basal and glucose-stimulated insulin secretion in pancreatic islets isolated from obese (fa/fa) Zucker rats and their homozygous lean (Fa/Fa) littermates.Research methods and proceduresIslets were isolated from 10- to 12-week-old rats and incubated for 45 minutes in glucose concentrations ranging from 3.3 to 16.7 mM with or without inhibitors of the cyclooxygenase or lipoxygenase pathways. Medium insulin concentrations were measured by radioimmunoassay, and islet production of the 12-lipoxygenase metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), was measured by enzyme immunoassay.ResultsIn islets from lean animals, AA stimulated insulin secretion at submaximally stimulatory glucose levels (

The effect of leptin on insulin secretion is controversial due to conflicting results in the literature. In the present study, we incubated insulin-producing rat insulinoma INS-1 cells for 60 min and examined the effects of recombinant murine leptin (20 nmol/l). We found that leptin (0.1-100 nmol/l) did not affect the insulin response to glucose (1-20 mmol/l). However, when cells were incubated with agents that increase the intracellular content of cAMP, i.e., glucagon-like peptide-1 (100 nmol/l), pituitary adenylate cyclase activating polypeptide (100 nmol/l), forskolin (2.5 micromol/l), dibutyryl-cAMP (1 mmol/l), or 3-isobutyl-1-methylxanthine (100 micromol/l), leptin significantly reduced insulin secretion (by 34-58%, P < 0.05-0.001). In contrast, when insulin secretion was stimulated by the cholinergic agonist carbachol (100 micromol/l) or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (1 micromol/l), both of which activate protein kinase C, leptin was without effect. We conclude that leptin inhibits insulin secretion from INS-1 cells under conditions in which intracellular cAMP is increased. This suggests that the cAMP-protein kinase A signal transduction pathway is a target for leptin to inhibit insulin secretion in insulin-producing cells.

Evidence for regulation of circulating leptin by insulin is conflicting. Diabetes was induced in rats with streptozotocin (STZ; 40 mg.kg(-1).day(-1) x 2 days) to examine the effect of insulin-deficient diabetes and insulin treatment on circulating leptin. After 12 wk, plasma leptin concentrations in untreated rats were all < 0.4 ng/ml versus 4.9 +/- 0.9 ng/ml in control animals (P < 0.005). In rats treated with subcutaneous insulin implants for 12 wk, which reduced hyperglycemia by approximately 50%, plasma leptin was 2.1 +/- 0.6 ng/ml, whereas leptin concentrations were 6.0 +/- 1.6 ng/ml in insulin-implanted rats receiving supplemental injections of insulin for 4 days to normalize plasma glucose (P < 0.005 vs. STZ untreated). In a second experiment, plasma leptin was monitored at biweekly intervals during 12 wk of diabetes. In rats treated with insulin implants, plasma leptin concentrations were inversely proportional to glycemia (r = -0.64; P < 0.0001) and unrelated to body weight (P = 0.40). In a third experiment, plasma leptin concentrations were examined very early after the induction of diabetes. Within 24 h after STZ injection, plasma insulin decreased from 480 +/- 30 to 130 +/- 10 pM (P < 0.0001), plasma glucose increased from 7.0 +/- 0.2 to 24.8 +/- 0.5 mM, and plasma leptin decreased from 3.2 +/- 0.2 to 1.2 +/- 0.1 ng/ml (delta = -63 +/- 3%, P < 0.0001). In a subset of diabetic rats treated with insulin for 2 days, glucose decreased to 11.7 +/- 3.9 mM and leptin increased from 0.5 +/- 0.1 to 2.9 +/- 0.6 ng/ml (P < 0.01) without an effect on epididymal fat weight. The change of leptin was correlated with the degree of glucose lowering (r = 0.75, P < 0.05). Thus insulin-deficient diabetes produces rapid and sustained decreases of leptin that are not solely dependent on weight loss, whereas insulin treatment reverses the hypoleptinemia. We hypothesize that decreased glucose transport into adipose tissue may contribute to decreased leptin production in insulin-deficient diabetes.

The gut hormones, cholecystokinin (CCK) and truncated glucagon-like peptide 1 (GLP-1(7-36)amide or GLP-1) both stimulate insulin secretion and affect glucagon secretion in mice, but their effects on the secretion of other islet hormones have not been established in rodents. In the present study, we have examined the influence of the C-terminal octapeptide of CCK, CCK-8, and GLP-1 on the secretion of pancreatic polypeptide (PP) in the mouse by the use of a radioimmunoassay for rodent PP. Mice were injected intravenously with CCK-8 (doses in the range of 0.053-5.3 nmol/kg) or with GLP-1 (doses in the range of 1-32 nmol/kg) and blood was sampled at 2, 6 or 10 min after the injection. Controls were injected with saline. It was found that CCK-8 at 5.3 nmol/kg increases plasma levels of both PP and insulin when the sample was taken at 2 min, but not at 6 or 10 min, after injection. These effects were blocked by the selective CCKA-receptor antagonist, L-364,718 (2.4 micromol/kg). GPL-1 increased plasma insulin levels at 32 nmol/kg at 2 and 6 min after the injection, but plasma PP levels were unaltered. In conclusion, this study, using a newly developed radioimmunoassay for PP in rodents, shows that CCK-8 but not GPL-1 stimulated PP secretion in mice at dose levels where both peptides stimulate insulin secretion. Furthermore, PP secretion in response to CCK-8 showed a similarity with that of insulin in terms of dose- and time-response characteristics as well as sensitivity to CCKA-receptor antagonism.