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Cited by 431Diabetes Treatment and ManagementDiabetes Management and ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients.

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Ryysy, L, Häkkinen, A M, Goto, T, Vehkavaara, S, Westerbacka, J, Halavaara, J, Yki-Järvinen, H·2000·Diabetes
DOI 10.2337/diabetes.49.5.749
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Abstract

To determine causes of interindividual variation in insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and insulin doses for >1 year on combination therapy with bedtime NPH insulin and metformin. Insulin absorption (increase in free and total insulin over 8 h after a subcutaneous dose of regular insulin) and actions of intravenous (6-h 0.3 mU x kg(-1) x min(-1) euglycemic insulin clamp combined with [3-3H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: insulin dose range 10-176 U (mean 42 U, fold variation 17.6x) or 0.13-1.39 U/kg (0.44 U/kg, 10.7x), absorbed insulin 10.6x, action of subcutaneous insulin to suppress FFAs 7.5 x and to stimulate glucose metabolism (M value) 11.5x, body weight 67-127 kg (91 kg, 1.9x), liver fat 2-28% (12%, 14x), and visceral fat 179-2,053 ml (1,114 ml, 11.5x). The amount of insulin absorbed, measured as either free or total insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the insulin dose per se. The actions of absorbed insulin were, on the other hand, significantly correlated with the daily insulin dose (r = 0.70 for action on FFAs, P < 0.001, and r = -0.61 for M value, P < 0.005). Actions of subcutaneous and intravenous insulin to suppress FFAs were significantly correlated (r = 0.82, P < 0.001, R2 = 67%). Of the measures of adiposity, the percent hepatic fat was the parameter best correlated with the daily insulin dose (r = 0.76, P < 0.001). The percent hepatic fat was also significantly correlated with the ability of intravenous insulin to suppress endogenous glucose production (r = 0.72, P < 0.005). We conclude that the major reason for interindividual variation in insulin requirements in type 2 diabetes is the variation in insulin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitivity of endogenous glucose production to insulin.

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  • Previous studies by our group and others have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.

    “Previous studies by our group (9, 17-20) and others (7, 21, 22) have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.”

    From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [22]

    The Discussion reports a strong correlation between liver fat percentage and hepatic insulin sensitivity, supporting the liver portion of the claim. Our copy does not report a relationship between muscle triglyceride content and muscle insulin resistance; its mention of skeletal-muscle insulin resistance does not establish that relationship. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)

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  • The measurement of liver fat by proton spectroscopy has been validated against histologically determined lipid content and against estimates of fatty degeneration or infiltration by x-ray computer-assisted tomography.

    “This measurement has been validated against histologically determined lipid content 44 and against estimates of fatty degeneration or infiltration by x-ray computer-assisted tomography.38”

    From Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. (2008) · cites this paper as [38]

  • The associations between liver fat and hepatic insulin resistance have previously been reported by Bajaj et al in 14 type 2 diabetic patients, and by us in nondiabetic subjects and type 2 diabetic patients treated with insulin.

    “The associations between liver fat and hepatic insulin resistance have previously been reported by Bajaj et al, 62 who studied 14 type 2 diabetic patients, and by us in nondiabetic subjects 24,39 and type 2 diabetic patients treated with insulin. 36,38”

    From Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. (2008) · cites this paper as [38]

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1 of the 40 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Gidez LJ, Miller GJ, Burstein M, Eder HA: Analysis of plasma high density lipoprotein subclasses by a precipitation procedure: correlation with prepar- ative and analytical ultracentrifugation. In High Density Lipoprotein Method- ology Workshop, San Francisco, 1979.

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Authors
Ryysy, L., Häkkinen, A. M., Goto, T., Vehkavaara, S., Westerbacka, J., Halavaara, J., & Yki-Järvinen, H.
Affiliations
  • University of Helsinki (FI)
  • Department of Medicine, University of Helsinki, Finland.
ORCID
Goto, T
Venue
Diabetes
Publisher
American Diabetes Association
Published
2000-05-01
Volume
49
Issue
5
Pages
749-758
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.49.5.749
OpenAlex
W2132477505
Cited by
431
References
40
Citations by year
2025: 5 · 2024: 2 · 2023: 10 · 2022: 9 · 2021: 11 · 2020: 13 · 2019: 10 · 2018: 8 · 2017: 19 · 2016: 9 · 2015: 11 · 2014: 21 · 2013: 25 · 2012: 13
FWCI
13.30
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
type 2 diabetes, insulin requirement, insulin absorption, hepatic fat content, free fatty acids, insulin action, glucose metabolism, insulin resistance, visceral fat, adiposity, interindividual variability, insulin dose adjustment, metformin, NPH insulin, hepatic steatosis, hepatic insulin sensitivity, hepatic insulin secretion, hepatic insulin clearance
MeSH terms
Absorption, Adipose Tissue, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Fatty Acids, Nonesterified, Female, Glucose, Humans, Hypoglycemic Agents, Injections, Intravenous, Injections, Subcutaneous, Insulin, Liver, Male, Middle Aged

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