Diabetes Research and Clinical Practice, 14 (I 99I) S31-S46 0 1991 Elsevier Science Publishers

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Insulin resistance, insulin deficiency, and non-insulin-dependent diabetes mellitus* Erol

Cerasi

Department of Endocrinology and Metabolism. Hebrew University Hadassah Medical Center. Jerusalem, Israel

Summary Recent information suggests that type 2 diabetes mellitus (NIDDM) is associated with severe insulin resistance, but other information suggests that there is a hypoinsulinemic state. To investigate the nature of the insulin resistance, 10 newly diagnosed, mildly obese type 2 diabetics and 11 long-standing type 2 diabetics with secondary failure to sulfonylureas were studied. Insulin was given by continuous subcutaneous infusion (CSII) for two weeks. CSII produced near-normoglycemia after l-4 days in all patients with modest amounts of insulin (0.5-0.9 U/kg/24 h). These results demonstrate that whatever insulin resistance prevails in NIDDM, it does not prevent induction of normoglycemia by insulin. This suggests that either the insulin resistance is a secondary event caused by hyperglycaemia, or that NIDDM patients are hypoinsulinemic. In further studies in vitro, the effect of glucose on the rate of glycolytic glucose utilization by isolated rat soleus muscle and on hexose transport in rat skeletal myocyte line L8 were assessed. In the first case, an increase in glucose concentration led to a decrease in muscle glycolysis, and in the second case a hyperglycemic concentration of glucose led to a marked reduction in hexose transport, which was fully reversible within two hours. The clinical and in vitro results plus literature data suggest that insulin resistance can be overcome by insulin in NIDDM, and that P-cell responsiveness to glucose is greatly reduced in NIDDM, but the defect is restricted to the acute stimulatory phase of glucose induction of insulin release. If this defect can be corrected, acute insulin be cured notwithstanding the existence of insulin resistance.

Correspondence Metabolism, Jerusalem,

to: E. Cerasi,

Hebrew

University

Dept.

of Endocrinology

Hadassah

Medical

and

* The studies from the author’s laboratory were funded grants from the Wolfson Foundation, the Israel Academy Sciences

and

Humanities,

the United

States-Israel

will occur so that NIDDM

would

Introduction

Center,

Israel.

Science Foundation, Institut de Recherches Servier, and the George Grandis Endowment.

release

by of

Binational

Internationales

For the last decade-and-a-half, diabetologists have been exposed to substantial data which suggest that severe insulin resistance is the main trait of type non-insulin-dependent diabetes mellitus 2, (NIDDM). In addition to implications regarding the pathogenesis of the disease, this has led to a negative attitude regarding insulin treatment in NIDDM. Indeed, if the data from hyperinsulinemic clamp studies can be extrapolated to the clinical

S38

situation, sulin

only suprapharmacological

could

reduce

the

blood

doses of inglucose

in these

night fast. Plasma glucose concentrations were normalized before the test using iv insulin or CSII;

patients. We and others [l-3] have consistently demonstrated that insulin output is severely reduced in

insulin was withdrawn glucagon administration.

NIDDM,

injected

and suggested

that hyperinsulinemia

a reflection of the hyperglycemia, indication of hyperfunctioning

is

rather than the p-cells [4]. The

recent demonstration by Hales and co-workers [5] that much of the circulating insulin-like material in NIDDM

consists

of proinsulin

and its cleavage

intermediates reinforces the view that NIDDM is a hypoinsulinemic state. The above considerations do not negate the presence of insulin resistance. In this paper, however, I will present evidence which suggests that such insulin resistance results from the response of a physiological regulatory mechanism to hyperglycemia. It will be shown that this phenomenon is rapidly reversible, allowing optimal control of blood glucose with moderate doses of insulin in lean as well as obese NIDDM patients.

blood

samples,

tinuation

1 mg of glucagon

iv. Glucose

frequently.

at least 45 min before After obtaining two basal

and C-peptide

These tests were repeated

was

rapidly

were measured after discon-

of CSII.

In both groups, ed by CSII

near-normoglycemia

following

was achiev-

a few days of adaptation.

CSII was continued for a further 14 days; thus all patients were near-normoglycemic for at least 2 weeks. Near-normoglycemia is defined as fasting blood glucose