Hillevi Larsson

Plasma Leptin Levels Correlate to Islet Function Independently of Body Fat in Postmenopausal Women

It has previously been demonstrated that plasma leptin correlates to body fat content. Increased body fat content is accompanied by low insulin sensitivity, which is compensated with increased insulin secretion. We therefore studied whether plasma levels of leptin also correlate to insulin secretion and sensitivity in humans. Therefore, we examined insulin sensitivity by the euglycemic-hyperinsulinemic clamp technique and measured the insulin response to intravenous arginine (5 g) at fasting and 14 mmol/l glucose in postmenopausal women. Percent body fat content was determined with impedance measurements. Log plasma leptin significantly correlated to percent body fat (r = 0.84, P < 0.001). In women with normal glucose tolerance (n = 36), partial correlation studies controlling for body fat content revealed significant correlations between log plasma leptin and fasting insulin levels (r = 0.39, P = 0.029), the insulin response to arginine at both glucose levels (r = 0.38 and r = 0.37, P < 0.036 for both), and the glucose potentiation of arginine-stimulated insulin secretion (r = 0.40, P = 0.025). In contrast, in women with impaired glucose tolerance (n = 17), these correlations were not significant. Plasma leptin did not correlate with insulin sensitivity independently of body fat content. To study whether the correlation between leptin and insulin would be explained by insulin stimulating leptin secretion, we examined plasma leptin during hyperinsulinemic conditions (689 ± 41 pmol/l), under both euglycemia (5.0 mmol/l, n = 10) and hypoglycemia (2.5 mmol/l, n = 7). However, under both these conditions, plasma leptin was unaltered. In conclusion, plasma leptin 1) reflects body fat content and 2) correlates to insulin secretion independently of percent body fat in postmenopausal women with normal glucose tolerance.

GLP-1 Tablet in Type 2 Diabetes in Fasting and Postprandial Conditions

OBJECTIVE To examine the absorption of glucagon-like peptide (GLP)-1(7-36) amide from the buccal mucosa of type 2 diabetic patients. Previously, the effects of the peptide have been studied following intravenous and subcutaneous injection. Now, a mucoadhesive, biodegradable buccal GLP-1 tablet (9 mm) containing 119 nmol has been developed as a possible alternative to injection. RESEARCH DESIGN AND METHODS A total of 10 type 2 diabetic patients received a single tablet under fasting conditions and before a standard meal in this randomized placebo-controlled study. RESULTS The mean peak GLP-1 concentration was 125.1 pmol/l and occurred 30 min after application. The mean placebo-adjusted area under the curve was 5,334 min pmol/l, consistent with a relative bioavailability of 6% vs. intravenous injection and 42% vs. subcutaneous injection. The half-life of total peptide activity after buccal administration was 17 min. The placebo-adjusted glucose concentrations decreased by 1.4 mmol/l in fasting experiments and by 4.2 mmol/l after a standard mixed meal. In the fasting state at 30 min, plasma insulin increased by 185% and glucagon decreased by 20%, consistent with the increase in plasma GLP-1 concentrations. The peptide exerted a significant insulinotropic effect during meals (calculated as an insulinogenic index, 0–120 min; 84.1 vs. 45.7 in placebo experiments). CONCLUSIONS Potentially therapeutic plasma levels of GLP-1 were achieved after administration of a single buccal tablet in type 2 diabetic patients. The peptide had a marked glucose-lowering effect during the first 2 h. This new GLP-1 tablet may become a feasible alternative treatment for type 2 diabetic patients, although a more prolonged pharmacokinetic profile is required.

Potential Therapeutic Levels of Glucagon-Like Peptide I Achieved in Humans by a Buccal Tablet

OBJECTIVE Glucagon-like peptide I(7–36) (GLP-I) amide, an endogenous incretin, has been identified as a potential adjunct to the treatment of NIDDM and has been studied following intravenous and subcutaneous injection. A mucoadhesive buccal GLP-I tablet containing 119 nmol has been developed to provide transmucosal absorption as a possible alternative to injection treatment. RESEARCH DESIGN AND METHODS Eight healthy volunteers received a single tablet under fasting conditions in this randomized double-blind placebo-controlled study. A total GLP-I immunoreactivity was measured using COOH-terminal radioimmunoassay (RIA) (total peptide activity) and NH2-terminal RIA (active, nondegraded peptide). RESULTS The mean (± SE) peak GLP-I concentration was 117 ± 19 pmol/l and occurred 30 ± 4 min after application. The mean placebo-adjusted area under curve was 8,145 ± 873 pmol · min−1 · l−1, consistent with a relative bioavailability of 7% versus intravenous injection and 47% versus subcutaneous injection. The levels of active peptide increased in parallel with total GLP-I. Half-life of peptide activity after buccal administration was 27 and 24 min measured with COOH-terminal and NH2-terminal RIA, respectively. Placebo adjusted insulin concentrations increased to a peak of 252 ± 57 pmol/l, glucose decreased 1.4 ± 0.2 mmo/l, and glucagon decreased 17 ± 3 ng/l, consistent with the increase in plasma GLP-I concentrations. CONCLUSIONS Therapeutic plasma levels of GLP-I in humans were achieved after a single buccal tablet. No increased degradation of GLP-I was found in the buccal mucosa compared to subcutaneous tissue. This alternative treatment form may be feasible in in the future for NIDDM.

Regulation of circulating leptin in humans.

In the early 1950s, the ob/ob mouse was described (I). Later extensive metabolic studies have shown that the syndrome of this mouse consists of massive obesity in conjunction with hyperphagia, insulin resistance, hyperinsulinemia, development of noninsulin-dependent diabetes mellitus (NIDDM), cold intolerance, and infertility (2). Parabiosis studies in the 1950s and 1960s also revealed that the cause of the syndrome is the deficiency of a circulatory factor, rather than overproduction of a factor, since lean mice in parabiosis with obese mice were found to reduce the weight of the obese animals (2-4). Finally, by the end of 1994, the gene coding for the factor lacking in the ob/ob mice was cloned (5) and in 1995 it was shown that administration of the protein product of this gene, leptin, normalized the hyperphagia, the massive obesity and the huge hyperinsulinemia in these animals (6-8).

Islet dysfunction in obese women with impaired glucose tolerance

Insulin sensitivity and islet function were examined in 22 obese women: 11 with normal glucose tolerance (mean +/- SD body mass index [BMI], 32.2 +/- 2.8 kg/m2) and 11 with impaired glucose tolerance (BMI, 30.1 +/- 2.2 kg/m2). Thirteen non-obese women with normal glucose tolerance (BMI, 20.9 +/- 1.3 kg/m2) served as controls. All women were 58 to 59 years of age. Insulin sensitivity was measured with the euglycemic, hyperinsulinemic clamp. Insulin secretion was studied after intravenous arginine (5 g) at fasting, and at blood glucose levels of 14 and greater than 25 mmol/L. Insulin sensitivity was higher in non-obese (99.8 +/- 11.5 nmol/kg/min/pmol insulin/L) than in obese subject (P < or = .002), but did not differ between obese subjects with normal versus impaired glucose tolerance (47.2 +/- 8.8 v 45.5 +/- 5.2 nmol/kg/min/pmol insulin/L, difference not significant [NS]). Obese subjects with normal glucose tolerance had a higher insulin response to both glucose (P < or = .004) and arginine (P < or = .02) than nonobese women, and higher glucose potentiation of insulin secretion, slopeAIR (P = .05). Compared with obese subjects with normal glucose tolerance, the obese subjects with impaired glucose tolerance had a lower insulin response to glucose (P = .03) and to arginine at blood glucose levels of 14 mmol/L (P = .03), as well as a lower slopeAIR levels ( P = .03). Fasting glucagon was higher in obese subjects with normal glucose tolerance than in non-obese subjects with normal glucose tolerance (P = .006). In obese subjects with impaired glucose tolerance, the glucose inhibition of glucagon secretion, slope AGR, was lower than in obese subjects with normal glucose tolerance (P = .04). Thus, obese subjects with impaired glucose tolerance have altered glucose modulation of islet function, mainly manifested as reduced slope AIR and slope AGR, yet insulin sensitivity is not different than in equally obese subjects with normal glucose tolerance. We therefore conclude that islet dysfunction, and not a further reduction of insulin sensitivity, determines the development of impaired glucose tolerance in obesity.

Fasting blood glucose in determining the prevalence of diabetes in a large, homogeneous population of Caucasian middle‐aged women

Abstract. Objectives. To determine the usefulness of a single, fasting blood glucose (FBG) value in measuring the prevalence of diabetes mellitus in a large, homogeneous population.

Leptin : A regulator of islet function? : Its plasma levels correlate with glucagon and insulin secretion in healthy women

It has previously been demonstrated that plasma leptin correlates to body fat content. It has also been demonstrated that in subjects with normal glucose tolerance, circulating leptin correlates to circulating insulin and to insulin secretion and that these relations are independent of body fat. However, whether leptin also covaries with other islet hormones is not known. We therefore studied the relation between plasma levels of leptin and glucagon secretion and circulating pancreatic polypeptide (PP) in healthy humans. Arginine was injected intravenously (5 g) at fasting and at 14 and 28 mmol/L, glucose in 71 postmenopausal women with normal glucose tolerance. In a multivariate analysis controlling for the influence of the body mass index, we found that circulating leptin correlated significantly to fasting insulin (r = .38, P = .002), and to circulating insulin at 14 mmol/L glucose levels (r = .29, P = .0019) and 28 mmol/L glucose (r = .32, P = .009), as well as to the insulin response to arginine at all three glucose levels (r > .30, P < .013). Circulating leptin, independently of the body mass index, also correlated to fasting glucagon (r = .31, P = .012) and to the glucagon response to arginine at all three glucose levels (r > .28, P < .038). In contrast, circulating leptin did not correlate to plasma glucagon at 14 or 28 mmol/L glucose or to plasma levels of PP. We conclude that circulating leptin correlates to the secretory capacity of both glucagon and insulin but not to the reduction of plasma glucagon during hyperglycemia or to PP in a large group of postmenopausal women. This suggests that islet function is related to circulating leptin in humans.

Androgen Activity as a Risk Factor for Impaired Glucose Tolerance in Postmenopausal Women

OBJECTIVE Low sex hormone–binding globulin (SHBG) has been proposed as a risk factor for NIDDM development in women. Our aim was to study the relationship between SHBG and androgen activity and glucose tolerance, as well as insulin sensitivity, in women with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS We studied 22 women with IGT and 46 women with normal glucose tolerance (NGT) aged 57–59 years. Free testosterone (androgen activity) was determined as the testosterone-to-SHBG ratio. A World Health Organization 75-g oral glucose tolerance test (OGTT) was performed, and insulin sensitivity was measured with a euglycemic-hyperinsulinemic clamp. RESULTS Fasting glucose (P = 0.021), 2-h blood glucose after the OGTT (P < 0.001), and fasting insulin (P = 0.009) were higher in the IGT group, while insulin sensitivity did not differ significantly between the two groups (P = 0.065). We found that SHBG levels were lower in the IGT group (P = 0.004), while the testosterone-to-SHBG ratio was higher in the IGT than in the NGT group (P = 0.004). Insulin sensitivity correlated negatively with testosterone-to-SHBG ratio in both groups. The correlation was higher in the IGT (r = −0.67, P = 0.001) than in the NGT group (r = −0.29, P = 0.047). In contrast, the 2-h blood glucose correlated with testosterone-to-SHBG ratio in the IGT (r = 0.66, P = 0.001) but not the NGT group (r = −0.04, NS). CONCLUSIONS Postmenopausal women with IGT have higher androgen activity than women with NGT, and the androgen activity correlates with the degree of glucose intolerance in IGT. Furthermore, in women with IGT, who have a high risk of NIDDM development, androgen activity seems to have an enhanced negative influence on insulin sensitivity. Therefore, androgen activity appears to be a risk factor for IGT.

Effects of Arginine on the Secretion of Insulin and Islet Amyloid Polypeptide in Humans

Islet amyloid polypeptide (IAPP) is synthesized in islet B cells and stored in the secretory granules. We examined whether IAPP and insulin are released in parallel in humans. Arginine hydrochloride (5 g) was injected intravenously at three glucose levels in 11 healthy 58-year-old female subjects. In the fasting state (plasma glucose, 4.9 ± 0.3 mM), serum insulin levels were 62 ± 8 pM and plasma IAPP levels were 5.9 ± 0.8 pM (r = 0.74, p < 0.01; insulin/IAPP ratio, 13.4 ± 3.6). The insulin response to arginine was 426 ± 84 pM (p < 0.001), whereas the IAPP response was 4.9 ± 1.8 pM (p < 0.01) (r = 0.93, p < 0.001). At 16.3 ± 0.5 mM glucose, the insulin response was increased to 1,516 ± 325 pM (p < 0.001), whereas the IAPP response was increased to 10.4 ± 2.8 pM (p < 0.01) (r = 0.91, p < 0.001). No further increases were seen at 35.0 ± 2.0 mM glucose. The ratios of insulin response/IAPP response, which represent the relative secretion of the two peptides, were 169 ± 31, 158 ± 17, and 162 ± 17, at the three glucose levels. Thus, the ratios of the insulin/IAPP responses to arginine were the same regardless of the glucose level, and the insulin and IAPP responses to arginine were highly correlated with each other at all glucose levels. We conclude that the two peptides are cosecreted in strict parallelism after arginine stimulation in humans over a wide range of glucose levels.

Habitual dietary intake versus glucose tolerance, insulin sensitivity and insulin secretion in postmenopausal women

Abstract. Larsson H, Elmståhl S, Berglund G, Ahrén B (Lund University, Malmö University Hospital, Malmö, Sweden). Habitual dietary intake versus glucose tolerance, insulin sensitivity and insulin secretion in postmenopausal women. J Intern Med;245: 581–591.