Metformin reduces insulin requirement in Type 1 (insulin-dependent) diabetes

Abstract

The effect of metformin on Type 1 (insulin-dependent) diabetes has been assessed with the artificial pancreas. Fourteen Type 1 diabetic patients of normal body weight received in addition to their usual insulin therapy 850 mg metformin or placebo three times a day for 4-6 weeks. The sequence was placebo-metformin in eight patients and metformin-placebo in the other six. On the last day of metformin or placebo treatment, an artificial pancreas was used for about 36 h to assess insulin requirement. There was a 25.8% reduction in insulin requirement during metformin management despite slightly lower blood glucose levels (5.25 +/- 0.20 versus 5.98 +/- 0.18 mmol/l, p less than 0.01). Maximum reduction (about 50%) occurred 2 h after both lunch and dinner. There was no nocturnal effect. A marked decrease in specific insulin binding before metformin was found (0.56 +/- 0.27% to 10(7) monocytes versus 2.82 +/- 0.75 of control subjects) and significant increase after metformin (1.36 +/- 0.36%, p less than 0.05). There were no significant changes in blood lactate, total and HDL-cholesterol, triglycerides and C-peptide levels. These results show that insulin receptor binding is diminished in Type 1 diabetes, perhaps as a consequence of higher peripheral blood insulin levels and that metformin can improve binding, and so reduce the amount of insulin needed to reach euglycaemia. The insulin sparing effect is greatest after meals, and interference with intestinal absorption of sugars may also be important. It follows that metformin could be usefully administered to Type 1 diabetic patients with unimpaired liver and renal function to reduce their insulin requirement.

Insulin requirement for the antihyperglycaemic effect of metformin

“…Thus the failure of metformin to reduce the hyperglycaemia in BB/S rats substantiates the view that a therapeutic concentration of metformin does not mimic the actions of insulin in conditions of severe insulinopenia (Sterne, 1969;Bailey, 1992). However, the hypoglycaemic effect of exogenous insulin was augmented by metformin, as noted in other diabetic states (Lord et al, 1983;Pagano et al, 1983;Gin et al, 1985;Leblanc et al, 1987).…”

“…In particular, controversy exists concerning a possible association between the mode of action of metformin and that of insulin. Metformin cannot sustain life in totally pancreatectomized animals (Sterne, 1969), but it increases the blood glucose-lowering efficacy of insulin in hyperglycaemic and insulin resistant states (Pagano et al, 1983;Gin et al, 1985;Prager et al, 1986;Leblanc et al, 1987;Nosadini et al, 1987;Hother-Nielsen et al, 1989;Reaven et al, 1992). Thus it has been assumed, but not actually demonstrated, that the blood glucose-lowering effect of metformin requires the presence of insulin.…”

The use of metformin in type 1 diabetes: a systematic review of efficacy

“…In total, 47 of these publications were judged to be relevant to metformin therapy in type 1 diabetes. Analysis of publications revealed: 17 were observational studies with no random allocation and/or no comparator group [18,22,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]; 11 were reviews, letters or commentaries [43][44][45][46][47][48][49][50][51][52][53]; two did not contain any quantitative estimates of effects [54,55]; one concerned an outcome (erythrocyte binding of insulin) not judged relevant [56]; and four were abstracts of papers subsequently published [57][58][59][60]. Of the remaining 12 publications, one concerned insulin-requiring type 2 diabetes rather than type 1 diabetes (noted after translation) [61], and one covered a treatment period of fewer than 7 days [62].…”

“…• Observational; no random allocation and/or comparator groups (n=17) [18,22,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] • Review, commentary, letter (n=11) [43][44][45][46][47][48][49][50][51][52][53] • Insufficient numerical data (n=2) [54,55] • No relevant outcome (n=1) [56] • Abstract of later paper (n=4) [57][58][59][60] • No evidence of type 1 diabetes after translation (n=1)…”

The Benefits of Metformin Therapy During Continuous Subcutaneous Insulin Infusion Treatment of Type 1 Diabetic Patients

“…Most of these studies have been small (11), were uncontrolled (12), or were cross-over trials of short duration (10). Even in one previous trial involving the administration of insulin by CSII, the duration of treatment was only 3 weeks (19), and during this period, IR was not modified.…”