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Risks of Intensive Management of NIDDM: The Insulin Hypothesis |

Glucose Control and Insulin Resistance in Non-Insulin-dependent Diabetes Mellitus

Henry R. Robert, MD
[+] Article, Author, and Disclosure Information

From the University of California, San Diego, La Jolla, California, and the San Diego Veterans Affairs Medical Center, San Diego, California. For the current author address, see end of text. Note: This article is one of a series of articles comprising an Annals of Internal Medicine supplement entitled “Risks and Benefits of Intensive Management in Non-Insulin-dependent Diabetes Mellitus: The Fifth Regenstrief Conference.” To view a complete list of the articles included in this supplement, please view its Table of Contents. Acknowledgment: The author thanks Dr. Charles Clark for his constructive comments and advice. Grant Support: By the Medical Research Service, Department of Veterans Affairs, and the Veterans Affairs Medical Center, San Diego, California. Requests for Reprints: Robert R. Henry, MD, Veterans Affairs Medical Center, San Diego (V-111G), 3350 La Jolla Village Drive, San Diego, CA 92161.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;124(1_Part_2):97-103. doi:10.7326/0003-4819-124-1_Part_2-199601011-00004
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Chronic hyperglycemia is implicated in the pathogenesis of microvascular, neurologic, and macrovascular complications of diabetes.Recent studies prove that near-normal glycemic control in insulin-dependent diabetes mellitus (IDDM) reduces the risk for the development and progression of microvascular and neurologic complications. With the expectation of comparable benefits, similar glycemic goals have been advocated for the management of non–insulin-dependent diabetes mellitus (NIDDM). However, using intensified insulin therapy to achieve near-normal glycemia in NIDDM may be problematic because of basic differences in the pathophysiology of the two types of diabetes. Insulin resistance is a major contributor to the development of hyperglycemia in NIDDM and may prevent attainment of normoglycemia in most patients who are using the conventional approaches of diet, exercise, and oral hypoglycemic therapy. Near-normal glycemia in patients with NIDDM can usually be achieved with exogenous insulin but often requires large doses to overcome the insulin resistance. Intensive insulin therapy normalizes glycemia by decreasing hepatic glucose output and improving peripheral glucose uptake and may also improve insulin resistance and insulin secretion by reducing hyperglycemic glucotoxicity. However, large doses of exogenous insulin are associated with hyperinsulinemia and weight gain, but these effects may be minimized by combining insulin with other forms of therapy, for example, oral antidiabetic agents. When intensive management is instituted, the dose of exogenous insulin should be kept as low as possible. To do this, therapy for NIDDM must be part of a multifaceted approach combining insulin therapy with other effective forms of treatment such as counseling on diet and exercise therapy and the use of oral antidiabetic agents.


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Figure 1.
Mechanisms of hyperglycemia in NIDDM.

The X on each arrow indicates the presence of a defect that contributes to elevated glucose levels (Reproduced from Henry RR. Prospects for primary prevention of type II or non–insulin-dependent diabetes mellitus. Diabetes Reviews International. 1994; 3:2-5, with permission.).

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Figure 2.
Mean ± SE rates of basal hepatic glucose output in 14 subjects with NIDDM before and after intensive insulin therapy and in age-matched control subjects.

(Reproduced from reference 13 with permission.).

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Figure 3.
Mean in vivo dose-response curves for the control subjects (▴) and subjects with NIDDM before ○ and after (●) intensive insulin therapy.

(Reproduced from reference 13 with permission.).

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Figure 4.
Correlation of total weight gain with total insulin dose (A) and mean serum insulin level (B) at study completion.rPrP

For panel A, = 0.62, < 0.02; for panel B, = 0.67, < 0.01. (Reproduced from reference 14 with permission.).

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Figure 5.
Mean levels of basal hepatic glucose output (A) and peripheral glucose uptake (B) before and after 6 months of intensive insulin therapy in 14 subjects with NIDDM.

(Reproduced from reference 14 with permission.).

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Figure 6.
Mean diurnal blood glucose level (top) and glycosylated hemoglobin level (bottom) in the control group (+); morning-NPH group ○; evening-NPH group (●); two-injection group □; and multiple-injection group (■) before and after 12 weeks of treatment.

The normal reference range of glycosylated hemoglobin level is 4% to 6%. (Reproduced from reference 15 with permission.).

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