The effect of short-term α-glucosidase inhibition on carbohydrate and lipid metabolism in type II (noninsulin-dependent) diabetics

doi:10.1016/0026-0495(87)90035-7

Metabolism

Volume 36, Issue 5, May 1987, Pages 409-415

https://doi.org/10.1016/0026-0495(87)90035-7 Get rights and content

Abstract

With use of the α-glucosidase inhibitor bay g 5421 (acarbose), it is possible to improve glycemic profiles in diabetics without a concomitant increase in insulin levels or weight reduction. We have taken advantage of this feature to test whether an improvement in glycemic control alone can ameliorate some of the known abnormalities of type II diabetes (ie, impaired insulin secretion, elevated rate of basal hepatic glucose output, peripheral insulin resistance). We have studied eight type II diabetics (mean ± SE fasting serum glucose 193 ± 25 mg/dL) before and after 2 weeks of acarbose therapy (100 mg with each meal). Assessment of endogenous insulin secretion, peripheral and hepatic insulin sensitivity, and adipose tissue lipoprotein lipase (ATLPL) activity were performed. Results showed (1) significant lowering of postprandial glucose excursions above basal but no change in basal serum glucose levels, (2) marked reduction in fasting and day-long triglyceride levels and in spite of a reduction in ATLPL activity, (3) an increase in hepatic sensitivity to insulin's ability to suppress hepatic glucose output, and (4) no effect on peripheral insulin sensitivity. In conclusion, inhibition of carbohydrate digestion with α-glucosidase inhibitors ameliorates many of the metabolic abnormalities in type II (noninsulin-dependent diabetics), suggesting that agents of this type can be of therapeutic value.

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The digestion of carbohydrates is a complex phenomenon involving various metabolic enzymes. In the enzyme machinery responsible for this event, α-glucosidase and α-amylase are commonly used for breaking down oligosaccharides into their monomeric glucose units, which are the absorbable form taken up by transporters on the intestinal epithelium and transferred into the blood.39 Because high blood glucose facilitates susceptability to type 2 diabetes and its subsequent complications, preventing elevations in blood glucose is critical for diabetes therapy.
Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts
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Citation Excerpt :
In this other cohort, we also found that homozygous carriers had markedly higher levels of circulating acetate, which was likely only detectable due to the lack of fasting in these participants. Notably, the effect of the naturally occurring specific loss of SI function seemed to be greater on weight and levels of triglycerides compared with drug-induced unspecific inhibition of α-glucosidases by acarbose, voglibose, or miglitol,32–38 and the impact of loss of SI function on triglyceride levels was equal to the reported effect of the lipid-lowering drug statins.39,40 Moreover, altered high-density lipoprotein metabolism among homozygous carriers suggested increased health-promoting removal of cholesterol from extrahepatic tissues.
The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency.
The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings.
Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], –2.0 [0.5] kg/m²; P = 3.1 × 10^–5), body weight (–4.8 [1.4] kg; P = 5.1 × 10^–4), fat percentage (–3.3% [1.0%]; P = 3.7 × 10^–4), fasting triglyceride (–0.27 [0.07] mmol/L; P = 2.3 × 10^–6), and remnant cholesterol (–0.11 [0.03] mmol/L; P = 4.2 × 10^–5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10^–26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test.
These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate.
Acarbose attenuates postprandial hyperlipidemia: investigation in an intestinal absorptive cell model
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Oral administration of rac-α-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: A placebo-controlled pilot trial
1999, Free Radical Biology and Medicine
α-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with α-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) α-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different α-lipoic acid groups, all subjects receiving ALA were combined in the “active” group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of α-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.
Effect of acarbose on postprandial lipid metabolism in type 2 diabetes mellitus
1998, Diabetes Research and Clinical Practice
The effect of acarbose, an α-glucosidase inhibitor, on postprandial glucose and lipid metabolism was investigated in patients with type 2 diabetes mellitus. Twenty patients (10 men and 10 women) with type 2 diabetes mellitus were studied. A test meal was taken with or without 100 mg of acarbose. The levels of plasma glucose, and serum immunoreactive insulin, lipids, apolipoproteins, and remnant-like particle cholesterol were investigated. Acarbose inhibited the postprandial increase of both plasma glucose and serum immunoreactive insulin. Acarbose also significantly suppressed the increase of serum triglycerides at 60, 90, and 120 min (P<0.05 to P<0.01), and the increase of serum remnant-like particle cholesterol at 60 and 120 min (P<0.05). Acarbose inhibited the postprandial decline of apolipoprotein C-II, and decreased the postprandial serum apolipoprotein C-III level. These results suggest that acarbose may improve postprandial hyperlipidemia as well as postprandial hyperglycemia in patients with type 2 diabetes mellitus.
Improvement of insulin sensitivity and dyslipidemia with a new α- glucosidase inhibitor, voglibose, in nondiabetic hyperinsulinemic subjects
1996, Metabolism: Clinical and Experimental
This study was undertaken to investigate the effect of voglibose, a new α-glucosidase inhibitor, on glucose and lipid metabolism in nondiabetic hyperinsulinemic subjects. Sixteen nondiabetic subjects with hyperinsulinemia participated in the study. They were divided into two groups of eight subjects with normal (NGT) and impaired (IGT) glucose tolerance. A meal tolerance test and a 75-g oral glucose tolerance test (OGTT) were performed at the beginning (baseline phase) and end (treatment phase) of the 12-week treatment. Serum lipid levels were measured every 4 weeks throughout the treatment phase and follow-up phase (8 weeks). All patients received 10.2-mg tablet of voglibose before each test meal (3 tablets per day). We also measured insulin sensitivity using a steady-state plasma glucose (SSPG) method in eight normotensive hyperinsulinemic subjects and in eight age- and body mass index (BMI)-matched control subjects before and after the drug treatment. Voglibose significantly decreased the responses of plasma glucose and insulin on the meal tolerance test. The area under the curve for 2-hour insulin during the 75-g OGTT decreased after treatment, whereas that for 2-hour glucose did not change before and after treatment. SSPG was reduced after treatment, indicating improvement of insulin sensitivity. Moreover, treatment with voglibose resulted in a significant decline of triglyceride level and an elevation of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. These values returned to near-baseline levels after the drug was discontinued. Consequently, we conclude that this agent not only has a direct hypoglycemic effect through decreased absorption of carbohydrate, but also a hypoinsulinemic and hypolipidemic effect via improved insulin sensitivity.

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The effect of short-term α-glucosidase inhibition on carbohydrate and lipid metabolism in type II (noninsulin-dependent) diabetics

Abstract

Metabolism

Am J Med

Receptor and postreceptor defects contribute to the insulin resistance in non-insulin resistance in non-insulin dependent diabetes mellitus

J Clin Invest

Potentiation of insulin secretory responses by plasma glucose levels in man: Evidence that hyperglycemia in diabetes compensates for impaired glucose potentiation

J Clin Endocrinol Metab

Metabolic effects of very low caloric diet (VLCD) therapy in obese Type II diabetics (NIDDM)

Clin Res

The acute and chronic effects of sulfonylurea therapy in Type II diabetics

Diabetes

Insulin treatment reverses the insulin resistance of Type II diabetes mellitus

Diabetes Care

Scope and specificity of Acarbose in slowing carbohydrate absorption in man

Diabetes

Acarbose treatment of non-insulin dependent diabetes mellitus

Arch Intern Med

Classification and diagnosis of diabetes mellitus and other categories of glucose tolerance

Diabetes

Glucose clamp technique: A method for quantifying insulin secretion and resistance

Am J Physiol

Gluconeogenesis: Methodological approaches in vivo