Search

Objective: No specific treatment for oropharyngeal dysphagia related to diabetic neuropathy has been described to date. Chemical myotomy of the cricopharyngeus (CP) muscle by botulinum neurotoxin type A (BoNT/A) has been effective in reducing or abolishing dysphagia associated with upper esophageal sphincter (UES) hyperactivity of different etiologies. In the present study, we evaluated the efficacy of BoNT/A injections into the CP muscle in diabetic patients with severe oropharyngeal dysphagia associated with diabetic autonomic and/or somatic peripheral neuropathy., Research Design and Methods: Twelve type 2 diabetic patients with severe dysphagia for both solid and liquid foods associated with autonomic and/or peripheral somatic neuropathy were investigated. Swallowing function was evaluated by clinical examination, videofluoroscopy, and simultaneous needle electromyography (EMG) of the CP and pharyngeal inferior constrictor (IC) muscles. Clinical evaluation using a four-level dysphagia severity score was performed every other day for the 1st week and thereafter every other week until week 24. Videofluoroscopy and EMG follow-up were carried out at week 1, 4, 12, 16, 18, and 24 after BoNT/A injection. BoNT/A was injected percutaneously into the CP muscle under EMG control., Results: BoNT/A induced the complete recovery of dysphagia in 10 patients and had a significant (P = 0.0001, ANOVA) improvement in 2 patients within 4 +/- 1.1 days (range 3-7). Clinical improvement was confirmed by videofluoroscopy and EMG., Conclusions: Our findings suggest a potential benefit from BoNT/A treatment in dysphagia associated with diabetic neuropathy. Randomized controlled trials are needed to confirm this observation.

Objective: To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas., Research Design and Methods: A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment., Results: Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients., Conclusions: The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight.

The effects of the two groups of oral agents on insulin receptors were studied in several types of cells in tissue culture: MCF-7 human breast cancer cells, IM-9 human lymphocytes, human fibroblasts, and H-35 rat hepatoma cells. In none of these cells did the four sulfonylureas tested, tolbutamide, glibenclamide (glyburide), gliclazide, and glisolamide, have any significant effects on insulin binding to its receptor. In contrast the two biguanides tested, phenformin and metformin, increased insulin binding in all cell types by 44 to 101%. These studies raise the possibility, therefore, that biguanides may have a direct effect on insulin receptors and this effect may account for the known effects of biguanides to lower elevated blood sugar levels in diabetic patients.

Secondary failure to oral hypoglycemic agents (OHAs) is a possible outcome for non-insulin-dependent diabetes mellitus (NIDDM) patients and poses a serious therapeutic problem. In this study, we evaluated the effect of adding a single bedtime low-dose NPH insulin injection to the previous ineffective sulfonylurea therapy in 23 NIDDM patients with true secondary failure to OHAs. This treatment schedule was conducted for 3 mo by 18 patients (78%) who completed the study. In these patients, the addition of NPH insulin (0.2 +/- 0.01 IU/kg body wt) greatly decreased fasting and postprandial plasma glucose (P less than .001) and glycosylated hemoglobin (P less than .005). No weight gain was observed in any of the patients studied. Five patients dropped out: 2 patients (9%) due to insufficient compliance, 2 patients (9%) due to the multiple insulin injections required to achieve good metabolic control, and 1 patient (4%) due to recurrent hypoglycemic episodes. No correlation was observed between glucagon-stimulated C-peptide values and amelioration of metabolic control. In conclusion, most NIDDM patients with secondary failure to OHAs may be successfully treated with the addition of a single low-dose bedtime NPH insulin injection, and residual beta-cell function evaluation is not able to predict the effectiveness of the combined treatment.

This study was performed to assess whether the albumin excretion rate (AER) measured in overnight urine (N-AER) and 24-h urine (24-h AER) gives comparable results. For this reason we evaluated N-AER and 24-h AER on the same day from 35 control subjects, 57 patients with insulin-dependent diabetes mellitus (IDDM), and 63 patients with non-insulin-dependent diabetes mellitus (NIDDM). AER values obtained from the two urine collection procedures were significantly different (P less than .01), with 24-h AER approximately 30% higher than N-AER. Moreover, when the same cutoff value (20 micrograms/min) was used to define the normal range, 21% of IDDM patients and 6.3% of NIDDM patients had on the same day normal N-AER and abnormal (greater than 20 micrograms/min) 24-h AER. Although N-AER values were significantly correlated to 24-h AER values (r = 0.67, P less than .001), it was not possible to assess an N-AER value able to predict a 24-h AER value greater than 20 micrograms/min. In conclusion, N-AER and 24-h AER cannot be used as an equivalent method to establish AER.

Metformin, a biguanide antidiabetic agent that can be administered either alone or in combination with sulfonylureas, has been extensively used in Europe and Canada. The mechanism of action of metformin and other biguanides is not completely understood, but recent in vitro and in vivo studies suggest that metformin may act in part by both increasing the binding of insulin to its receptor and potentiating insulin action. Metformin, because of its chemical structure, does not interact with the liver and has a short half-life. Consequently, lactic acidosis, which is a rare complication of metformin, has not been associated with the proper use of this drug. In addition to its antidiabetic actions, metformin causes weight loss in obese diabetic patients and may be useful in managing associated lipid disorders.

We evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin (850 mg orally, b.i.d., for 4 days). Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects (+ 31%, P less than 0.05) and diabetic patients (+ 63%, P less than 0.01). Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded. By this mechanism, therefore, metformin may contribute to restoring insulin effectiveness in subjects with impaired insulin responsiveness.