Blood glucose response after oral lactulose intake in type 2 diabetic individuals

Abstract

BACKGROUND Lactulose is approved for the symptomatic treatment of constipation, a gastrointestinal (GI) complication common in individuals with diabetes. Lactulose products contain carbohydrate impurities ( e.g., lactose, fructose, galactose), which occur during the lactulose manufacturing process. These impurities may affect the blood glucose levels of individuals with type 2 diabetes mellitus (T2DM) using lactulose for the treatment of mild constipation. A previous study in healthy subjects revealed no increase in blood glucose levels after oral lactulose intake. However, it is still unclear whether the intake of lactulose increases blood glucose levels in individuals with diabetes. AIM To evaluate the blood glucose profile after oral lactulose intake in mildly constipated, non-insulin-dependent subjects with T2DM in an outpatient setting. METHODS This prospective, double-blind, randomized, controlled, single-center trial was conducted at the Clinical Research Center at the Medical University of Graz, Austria, in 24 adult Caucasian mildly constipated, non-insulin-dependent subjects with T2DM. Eligible subjects were randomized and assigned to one of six treatment sequences, each consisting of four treatments stratified by sex using an incomplete block design. Subjects received a single dose of 20 g or 30 g lactulose (crystal and liquid formulation), water as negative control or 30 g glucose as positive control. Capillary blood glucose concentrations were measured over a period of 180 min post dose. The primary endpoint was the baseline-corrected area under the curve of blood glucose concentrations over the complete assessment period [AUC baseline_c (0-180 min) ]. Quantitative comparisons were performed for both lactulose doses and formulations vs water for the equal lactulose dose vs glucose, as well as for liquid lactulose vs crystal lactulose. Safety parameters included GI tolerability, which was assessed at 180 min and 24 h post dose, and adverse events occurring up to 24 h post dose. RESULTS In 24 randomized and analyzed subjects blood glucose concentration-time curves after intake of 20 g and 30 g lactulose were almost identical to those after water intake for both lactulose formulations despite the different amounts of carbohydrate impurities (≤ 3.0% for crystals and approx. 30% for liquid). The primary endpoint [AUC baseline_c (0-180 min) ] was not significantly different between lactulose and water regardless of lactulose dose and formulation. Also with regard to all secondary endpoints lactulose formulations showed comparable results to water with one exception concerning maximum glucose level. A minor increase in maximum blood glucose was observed after the 30 g dose, liquid lactulose, in comparison to water with a mean treatment difference...

Novel insights into the pathogenic impact of diabetes on the gastrointestinal tract

“…• Prucalopride 259 • Psyllium 260 • Flaxseed 261 • Polyethylene glycol 262 • Lactulose 263 • Lubiprostone 264 Chronic diarrhoea • Correction of fluid and electrolyte imbalances • Antidiarrhoeal agents, which inhibit intestinal peristalsis and prolong transit time while reducing faecal volume (i.e., loperamide, 265 codeine, diphenoxylate 144 ). • Bile acid-biding resins (i.e., cholestyramine, colestipol and colesevelam; limited evidence) 265 • If present, correction of associated nutritional deficiencies of folate, calcium, zinc, iron, vitamin A and magnesium • Discontinue drugs potentially interfering with intestinal function (i.e., metformin, glucagon-like peptide…”

The potential role of lactulose pharmacotherapy in the treatment and prevention of diabetes

“…The intake of both 20 and 30 g of lactulose doses resulted in a slight net decrease in blood glucose concentrations of approx. −0.3 mmol/L from baseline as assessed by an overall negative area under the curve (AUC) of postprandial glucose response ( 18 ). Both studies showed that the oral intake of a single dose of lactulose remained largely stable in the blood glucose concentrations despite a continuous fasting period of 3 h either in healthy subjects or patients with T2D.…”

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“…Lactulose given via the oral route, either as crystals, marketed as a powder to be dissolved in water, or liquid syrup containing 10 g lactulose per 15 ml solution represents the standard mode of administration for the past decades [5,8]. During the manufacturing process of these commercial lactulose preparations, some impurities, including epilactose, lactose, galactose, fructose, tagatose and small amounts of unspecified or unknown sugars can arise [7], accounting for up to 3% of total carbohydrates in crystal lactulose and approximately 30% in liquid lactulose [10]. Theoretically, these impurities could lead to an increase in blood glucose levels with a possible impact on glycemic control in individuals with DM [8,10].…”

“…During the manufacturing process of these commercial lactulose preparations, some impurities, including epilactose, lactose, galactose, fructose, tagatose and small amounts of unspecified or unknown sugars can arise [7], accounting for up to 3% of total carbohydrates in crystal lactulose and approximately 30% in liquid lactulose [10]. Theoretically, these impurities could lead to an increase in blood glucose levels with a possible impact on glycemic control in individuals with DM [8,10]. On the other hand, the oral intake of unabsorbable disaccharides may affect carbohydrate metabolism by reducing transit time and, possibly, slowing down glucose absorption [11].…”

“…In the 2021 June issue of the World Journal of Diabetes, Pieber et al [10] have addressed this important issue, reporting results from a double-blind, randomized, controlled trial (RCT) conducted at the Medical University of Graz, Austria. Briefly, in this trial 24 adult mildly constipated, noninsulin-dependent subjects with type 2 (T2) DM received single doses of 20 g or 30 g lactulose, either as crystal or liquid formulation, water as negative control, or 30 g glucose as a positive control, in a crossover design.…”