Is Measuring Glucose the Right Way to Diagnose Diabetes?

Are we Missing the Fat?

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I am a cardiologist, not an endocrinologist or a diabetes expert. I didn’t even stay at a Holiday Inn Express last night, for those of you old enough to remember that commercial. But I wonder if we don’t have diabetes wrong.

Clinicians diagnose diabetes using glucose and hemoglobin A1C levels. Skeletal muscle is a major deposition site for glucose. Muscle then either uses the glucose as energy or stores it as glycogen. But compared to fat cells, skeletal muscle is insulin insensitive. I have discussed this earlier in a piece entitled “Every Patient with Hypertriglyceridemia is a Diabetic Want 2 B”. (1) That claim is based on the observation that many patients with high triglycerides and normal glucose and hemoglobin A1C levels develop diabetes-qualifying glucose levels years later. I have always explained this as follows:

- Insulin pushes free fatty acids into the fat cell,

- But the fat cell is so insulin sensitive,

- That even slight insulin resistance

- Allows free fatty acids to exit the fat cell

- And go to the liver where the free fatty acids are made into triglycerides.

The insulin issue is not recognized because we diagnose diabetes by glucose parameters.

This thought process means that “pre-diabetes”, diagnosed by glucose and A1C, is really an oxymoron. Sure, it’s pre-diabetes by glucose parameters, but not by fat cell parameters. I remember Ralph DeFronzo, MD, a pioneer in diabetes research, saying in a lecture that when someone qualified to be labelled as pre-diabetic, they had already lost 50% of their beta cells’ insulin secretory capacity.

Clinically, pre-diabetes is a problem.

- When the hemoglobin A1C is elevated, meaning that the hemoglobin protein has been glycosylated, other proteins in the body are also being glycosylated. These can include components of the LDL particle, making the particle more irritating to the endothelium. This glycosylation is complex, and beyond my comprehension, but glycosylation of other proteins might contribute to aging. (2)

- The Early ACS (Acute Coronary Syndrome) Trial determined the diabetes status of 879 patients with non-ST segment elevation myocardial infarctions (3) About 50% of these patients had some form of glucose intolerance: 32.5% had known diabetes, 12.2% had undiagnosed but definite diabetes and 8% had prediabetes diagnosed by a glucose of 110 to 126 mg/dL. So, prediabetes is not benign.

I think this theory, that we are lacking clinical markers of early insulin deficiency, explains some of our other risk factors. For examples:

- High density lipoprotein cholesterol (HDL-C) is one of the best lipid predictors of cardiovascular disease (CVD). Nobody talks about HDL anymore because both the AIM-HIGH (4) and HPS-Thrive (5) trials failed to demonstrate that raising HDL using niacin improved CVD outcomes. But that failure might have been because the low density lipoprotein cholesterol levels (LDL-C) were so low at study start (72.5 and 63 mg/dl, respectively) that it was too hard to obtain further benefit with HDL elevation. Also, AIM HIGH used very low dose niacin (50 mg) in the placebo tablet.(4) That was designed to produce flushing because niacin frequently produces flushing and the investigators feared that the absence of flushing in the placebo patients would “unblind” the study. The problem with that is my old niacin rule: “With niacin, the L goes with the H, and the H goes with the L”, meaning that you only need Low doses of niacin to raise the HDL, but you need High doses of niacin to lower the LDL. The HDL-C levels increased in both the placebo and niacin groups in AIM-HIGH from 34.9 to 39.1 and from 34.5 to 44.1 mg/dl, respectively, and this might have help conceal any niacin benefit on CVD outcomes. At any rate, HDL-C levels are inversely related to triglyceride levels (TG). When TGs go up, HDL-C goes down, because the TGs displace the cholesteryl-ester from the HDL particle. The TG-rich HDL particles produced by this C for TG exchange are more readily catabolized and cleared. Since TGs are a marker of insulin resistance, low HDL-C is also a marker of insulin resistance.

- High sensitivity C reactive protein (hsCRP). hsCRP is a well-recognized marker of CVD risk, but hsCRP is directly related to waist circumference, (6) making hsCRP an expensive measure of belt size. Why for example, was the JUPITER Trial one of the first trials to show that statins can lead to diabetes.(7) JUPITER randomized subjects with hsCRP values over 2 mg/l and LDL-C values under 130 mg/dl to either rosuvastatin 20 mg daily or placebo. Rosuvastatin reduced CVD events by 39% and deaths by 18%, but also increased the number of new diabetics from 216 in the placebo group to 270 in the rosuvastatin group. That was only 54 new cases of diabetes in 8,901 patients randomized to rosuvastatin and followed a median of 1.9 years. But this was statistically significant. The risk of developing diabetes was more frequent in those who had diabetes risk factors at baseline including metabolic syndrome, glucose levels over 100 mg/dl, a body mass index over 30, and an A1C over 6%. There were no new cases of diabetes in subjects without these risk factors. But why did JUPITER find this statin/diabetes relationship when other studies had not? I think it’s because JUPITER recruited folks with high hsCRP, which is related to increased waist circumference, which is related to insulin resistance, which is related to prediabetes, which is related to altered fat metabolism. So, I think the altered fat metabolism is increasing the CVD risk. Supporting this interpretation is the observation that 41 % of the JUPITER participants had the metabolic syndrome, a diabetes precursor. I acknowledge that fat cells are inflammatory, and may be directly causing the inflammation and the elevated hsCRP, but I wonder if getting fat doesn’t cause the insulin resistance which raises the hsCRP.

- Hepatic steatosis (fatty liver) is increasing recognized as a CVD risk factor, (9) and is also related to insulin resistance, but again it is not totally clear what is the cart and what is the horse. Is the insulin resistance allowing free fatty acids to exit the fat cell and to get deposited in the liver or is the fat in the liver causing insulin resistance. My bias is that the fat cell is the perpetrator.

These three examples are considered “independent CVD risk factors” because we cannot measure, the pre-prediabetes.

We now say that “even lower is even better” for LDL-C. I wonder if we won’t soon say the same for hemoglobin A1C values. I know that the diabetes trials have failed to show a difference in cardiovascular outcomes between A1C values above or below 7%, but those studies achieved low A1C’s with exogenous insulin and insulin causes hypoglycemia and has many atherogenic properties. We have better diabetes treatment and prevention methods now.

So, what is the clinical import of these musings?

I think that clinicians should be much more aggressive treating the oxymoron, “prediabetes”. Clinicians should:

Weigh patients yearly and make it a big deal when a patient gains weight because “it’s easier to lose 1 pound 50 times, than 50 pounds once.”

Encourage people to exercise. Skeletal muscle has both insulin-independent and insulin-dependent mechanisms to take up glucose. Exercise can enhance the insulin independent mechanism meaning that exercise can enhance skeletal muscle glucose uptake even with early insulin resistance.

Have a low threshold for using the new and the old diabetes medications. Metformin is dirt cheap and reduced the onset of frank diabetes by 31% over 3 years compared to usual care in the Diabetes Prevention Study.(10) Metformin is also being studied as an anti-aging medication in part because it reduces inflammation. Hmmm.

Please remember that the above thoughts are just my musings. I did not stay at a Holiday Inn Express last night, or ever. Time and research will ultimately find the truth.

1. https://pauldthompsonmd.substack.com/p/diabetic-want-2-bs

2. Paton B, Suarez M, Herrero P, Canela N. Glycosylation Biomarkers Associated with Age-Related Diseases and Current Methods for Glycan Analysis. Int J Mol Sci. 2021 May 28;22(11):5788. PMID: 34071388

3. Giraldez RR, Clare RM, Lopes RD, et al. Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome. Am Heart J 2013;165:918,925.e2.

4. AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med, 365 (2011), pp. 2255-2267

5. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med, 371 (2014), pp. 203-212

6. Santa-Paavola R, Lehtinen-Jacks S, Jääskeläinen T, Männistö S, Lundqvist A. The association of high-sensitivity C-reactive protein with future weight gain in adults. Int J Obes (Lond). 2022 Jun;46(6):1234-1240. PMID: 35260816

7. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. JUPITER Study Group.N Engl J Med. 2008 Nov 20;359(21):2195-207. PMID: 18997196

8. Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association.

9. Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, Cohen DE, Horton JD, Pressman GS, Toth PP; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease.Arterioscler Thromb Vasc Biol. 2022 Jun;42(6):e168-e185. PMID: 35418240

10. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. PMID: 11832527

#diabetes #insulin #insulinresistance #highsensitivityCRP #triglycerides #HDL #exercise