Insulin Glucagon Glucose

Here’s a fun watch that is of interest to diabetics. And nerds.

On the Hyperlipid BLOG (Insulin glucagon and protein) examined this study (Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012 Jan;122(1):4-12). The study looked at Diabetes as a disorder more related to glucagon than insulin. In particular, the Hyperlipid BLOG considered the blood sugar response of a diabetic to protein. I did the same thing myself here in this BLOG several times (Glucose Response to ProteinBlood Sugar Response to Proteins and Blood Sugar Responses Compared).

The paper presents the following lines of evidence for the claim,

Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence:

(a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency;

(b) hyperglucagonemia is present in every form of poorly controlled diabetes;

(c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency;

(d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia.

The insight that this may not be as much an insulin issue as a glucagon issue is a powerful one which may have application with medications to control Type 2 Diabetes. If giving exogenous insulin produces problems with Insulin Resistance, giving a medication which causes the body to produce less glucagon may have an opposite effect. It may be possible to develop a medication which downregulates glucagon indefinitely.

This has been tried in a 2017 Phase I drug study (Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes). Here is the full paper for the study (Effect of a glucagon receptor antibody (Jeremy Pettus MD. REMD‐477) in type 1 diabetes: A randomized controlled trial).

What is the cost (in other systems in the body) if glucagon is downregulated? 

Is eating 50g of Whey Protein a good replacement for the OGTT? I think it’s a much better choice than eating 75g of glucose.

Mice on an Ad Lib Keto Diet

Here is a nice paper from 2009 on mice fed an ad libitum ketogenic diet (Kennedy AR, Pissios P, Otu H, Roberson R, Xue B, Asakura K, Furukawa N, Marino FE, Liu FF, Kahn BB, Libermann TA, Maratos-Flier E. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1724-39. Epub 2007 Feb 13).

The study looked at:

C57BL/6 mice animals were fed one of four diets:

1) KD;

2) a commonly used obesogenic high-fat, high-sucrose diet (HF);

3) 66% caloric restriction (CR); and

4) control chow (C).

Calories were the same but weight was lower on the ketogenic diet.

Mice on KD ate the same calories as mice on C and HF, but weight dropped and stabilized at 85% initial weight, similar to CR.

In fact, they moved mice from the High Fat High Carb diet to the Ketogenic diet and had the following:

Animals made obese on HF and transitioned to KD lost all excess body weight, improved glucose tolerance, and increased energy expenditure. 

Even more along my own area of interest:

KD fed mice had a unique metabolic and physiological profile, exhibiting increased energy expenditure and very low respiratory quotient

The macronutrient composition of the diets was interesting:


Note this was not a high protein KD. I.e., The dietary advantage wasn’t protein. The percentage of calories from protein was the lowest on the KD – by far. This is a much higher level of fat than most people will tolerate and the protein level is pretty low.

Most telling was the body composition changes (Table 5).


The Chow fed mice were a bit over 10% heavier but at a lower % of Body Fat (13.5%) vs the Ketogenic fed mice. This can be attributed to the much lower protein consumption of the KD.

A contrasting study (Protein Leverage Hypothesis Counterpoint) showed an inflection point around 70% for fat where additional fat did not result in additional weight. In my opinion (study needed) – substituting protein for some of the fat should not be an issue.

The study concluded:

the effects that diet composition can have on metabolism and found that diets high in fat and low in carbohydrate do in fact lead to weight loss by increasing energy expenditure. 

Remarkably, animals eating ketogenic diet lost a small amount of weight and achieved the same weight and body composition as animals that were calorie restricted to 66% of usual daily intake.

In a related paper (Bielohuby M1, Menhofer D, Kirchner H, Stoehr BJ, Müller TD, Stock P, Hempel M, Stemmer K, Pfluger PT, Kienzle E, Christ B, Tschöp MH, Bidlingmaier M. Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein. Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E65-76) noted the same issue with KD :

One problem with ketogenic LC-HF diets is that it is difficult to attribute observed effects (e.g., loss of body weight) to either the presence of ketone bodies or to the normally very low protein content of these diets.

The ideal ketogenic diet for research purposes would be a LC-HF diet that is ketogenic but ensures the sufficient supply of protein at the same time. However, until now, it is not clear whether the absence of dietary carbohydrates per se or the absence of carbohydrates in combination with a specific abundance of the two other macronutrients, fat and protein, is required to induce ketosis.

Fat Stores Where/How?

Peter at the Hyperlipid BLOG has an interesting analysis of an interesting paper on fat storage in mice (On phosphorylating AKT within visceral fat). The study he looks at is (Narita T, Kobayashi M, Itakura K, Itagawa R, Kabaya R, Sudo Y, Okita N, Higami Y. Differential response to caloric restriction of retroperitoneal, epididymal, and subcutaneous adipose tissue depots in rats.  Exp Gerontol. 2018 Apr;104:127-137). The study looked at ad lib feeding of mice and the storage of fat in three White Adipose Tissues (WAT) depots in rats: retroperitoneal (rWAT), epididymal (eWAT) and subcutaneous (sWAT).

Peter’s interest is in fat storage based on insulin levels. The study compared ad libitum to calorie restricted eating in the mice. Peter concentrated on the ad libitum eating of the mice (not being all that interested in calorie restricted diets). Peter points out that it takes insulin to store fat in subcutaneous tissues but very little insulin to store fat in visceral fat. The study put it this way:

In all WAT depots, CR markedly upregulated the expression of proteins involved in FA biosynthesis in fed rats. In visceral WAT (rWAT and eWAT), hormone-sensitive lipase (lipolytic form) phosphorylation was increased by CR under fed conditions, and decreased by CR under fasted conditions. Conversely, in sWAT, hormone-sensitive lipase phosphorylation was increased by CR under fasted conditions. CR enhanced the effect of feeding on AKT activity in sWAT (indicative of a positive effect on insulin sensitivity) but not in rWAT or eWAT. These data suggest that CR improves lipid metabolism in an insulin signaling-dependent manner in sWAT only.

As Peter puts it:

This looks very much like one of the intrinsic differences between subcutaneous adipocytes and visceral adipocytes is that visceral adipocytes maintain insulin signalling at much lower levels of plasma insulin than do subcutaneous adipocytes. You have to store calories which arrive without insulin somewhere. Looks like this is the place!

I’m still of the opinion that visceral fat is what matters the most in reversal of Type 2 Diabetes. The Low Carb diet gets insulin levels low which reduces fat in general. See this article (A Grand Unified Theory of Polyunsaturated Fatty Acid Misbehaviour in Inflammatory Disease).

This article is actionable as well (Fatty liver and its treatment).

Alcohol and Weight Loss

I get asked a lot about alcohol and weight loss. Here’s a study which took a look at what happens to fat oxidation when alcohol is consumed (Siler SQ, Neese RA, Hellerstein MK. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am J Clin Nutr. 1999 Nov;70(5):928-36).


We used stable-isotope mass spectrometric methods with indirect calorimetry to establish the metabolic basis of changes in whole-body lipid balances in healthy men after consumption of 24 g alcohol.


Eight healthy subjects were studied and DNL (by mass-isotopomer distribution analysis), lipolysis (by dilution of [1,2,3,4-(13)C(4)]palmitate and [(2)H(5)]glycerol), conversion of alcohol to plasma acetate (by incorporation from [1-(13)C(1)]ethanol), and plasma acetate flux (by dilution of [1-(13)C(1)]acetate) were measured.


The fractional contribution from DNL to VLDL-triacylglycerol palmitate rose after alcohol consumption from 2 +/- 1% to 30 +/- 8%; nevertheless, the absolute rate of DNL (0.8 g/6 h) represented <5% of the ingested alcohol dose; 77 +/- 13% of the alcohol cleared from plasma was converted directly to acetate entering plasma. Acetate flux increased 2.5-fold after alcohol consumption. Adipose release of nonesterified fatty acids into plasma decreased by 53% and whole-body lipid oxidation decreased by 73%.


We conclude that the consumption of 24 g alcohol activates the hepatic DNL pathway modestly, but acetate produced in the liver and released into plasma inhibits lipolysis, alters tissue fuel selection, and represents the major quantitative fate of ingested ethanol.

It’s not so much that the alcohol itself gets turned to fat, it’s that alcohol inhibit lipolysis (fat burning).

Another Way to Reverse Diabetes

Here’s another way to reverse Type 2 Diabetes (E. L. Lim, K. G. Hollingsworth, B. S. Aribisala, M. J. Chen, J. C. Mathers, R. Taylor. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia, October 2011, Volume 54, Issue 10, pp 2506–2514). Here were the subjects:

Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m2, nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet.

Here are the results:

After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003).

Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%).

Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003).

The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min−1 m−2p < 0.001) and approached control values (0.62 ± 0.15 nmol min−1 m−2p = 0.42).

Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min−1 m−2).

Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03).

Other interesting factoids from the study. In Type 2 diabetics:

Beta cell function declines linearly with time, and after 10 years more than 50% of individuals require insulin therapy.

Here’s the data from the study.

VariableControlsBaselineWeek 1Week 4Week 8
Weight (kg)101.5 ± 3.4103.7 ± 4.599.7 ± 4.5*94.1 ± 4.3 *88.4 ± 4.3*†
BMI (kg/m2)33.4 ± 0.933.6 ± 1.232.3 ± 1.2*30.5 ± 1.2*28.7 ± 1.3*†
Fat mass (kg)36.2 ± 2.739.0 ± 3.536.6 ± 3.6 *31.7 ± 3.7 *26.3 ± 4.0*
ffm (kg)64.7 ± 3.864.7 ± 3.063.2 ± 3.162.4 ± 3.0 *62.1 ± 3.0*
Waist circumference (cm)105.0 ± 1.5107.4 ± 2.2104.4 ± 2.2*99.7 ± 2.4 *94.2 ± 2.5*†
Hip circumference (cm)109.8 ± 2.4109.5 ± 2.9108.3 ± 2.7*105.0 ± 2.6*99.5 ± 2.6*†
WHR0.96 ± 0.020.98 ± 0.020.97 ± 0.020.95 ± 0.010.95 ± 0.01

It is remarkable that the people lost mostly fat. The Fat Free Mass loss was only 2.6kg (about 6 lbs). The fat loss was 10 kg (about 22 lbs). That’s a pretty decent drop.

Low Carb?

This was neither a Low Carb nor Low Fat diet. It was a restricted calorie diet (600 calories a day). The macros were 46.4% carbohydrate, 32.5% protein and 20.1% fat; vitamins, minerals and trace elements; 2.1 MJ/day [510 kcal/day]; Optifast; Nestlé Nutrition, Croydon, UK. This was supplemented with three portions of non-starchy vegetables such that total energy intake was about 2.5 MJ (600 kcal)/day. 

It is remarkable how much fat was lost from the liver in just the first week.

Hepatic triacylglycerol content decreased by 30 ± 5% during week 1 of intervention (p < 0.001), becoming similar to control values (p = 0.75). It continued to decline throughout the intervention period to reach the normal range for non-obese individuals [20] (2.9 ± 0.2%; p = 0.003; Fig. 1), i.e. a total reduction of 70 ± 5%.

Most interestingly, the study after the study noted:

Following the intervention, participants gained 3.1±1.0 kg body weight over 12 weeks, but their HbA1c remained steady while the fat content of both pancreas and liver did not increase.

The conclusion matches my own hypothesis:

The data are consistent with the hypothesis that the abnormalities of insulin secretion and insulin resistance that underlie type 2 diabetes have a single, common aetiology, i.e. excess lipid accumulation in the liver and pancreas.

Giving Monkeys Diabetes

I listened to an interesting Break Nutrition podcast (Episode 13 – What happens to fructose-fed monkeys?) on a study of Rhesus Monkeys who were fed fructose meals (Bremer AA, Stanhope KL, Graham JL, Cummings BP, Wang W, Saville BR, Havel PJ. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetes. Clin Transl Sci. 2011 Aug;4(4):243-52). (Full PDF).

…a high-fructose diet in rhesus monkeys produces insulin resistance and many features of the metabolic syndrome, including central obesity, dyslipidemia, and infl ammation within a short period of time; moreover, a subset of monkeys developed type 2 diabetes

A Rhesus monkey used in the study is closer genetically to a human than the typical mouse study.

Numerous animal studies, mostly conducted in rodents, have shown that diets high in fructose produce metabolic perturbations associated with the metabolic syndrome and T2DM. 

However, important metabolic differences exist between rodents and primates, particularly with respect to lipoprotein metabolism,the major site of lipogenesis (liver vs. adipose), and the physiology of thermogenesis.

Therefore, the results of metabolic studies performed in primates are substantively more applicable to human physiology and medicine than those from rodent studies, underscoring the importance of developing standardized nonhuman primate models of insulin resistance for the study of metabolic syndrome and T2DM.

Kimber Stanhope was one of the authors of this study. See her other study on Fructose (Not All [Sugar] Is Bad).

The charts in the study are very interesting. Gabor discusses them on the podcast.

Am I Still a Diabetic?

That’s a challenging question since by most tests I am not a diabetic. I no longer take diabetic meds and have good control of my blood sugars. The Type 2 Diabetes ADA Diagnosis Criteria are any of the following:

  1. A hemoglobin A1c (HbA1c) level of 6.5% or higher; the test should be performed in a laboratory using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay, or
  2. A fasting plasma glucose (FPG) level of 126 mg/dL (7 mmol/L) or higher; fasting is defined as no caloric intake for at least 8 hours, or
  3. A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
  4. A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia (ie, polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis

I have changed the bullet-ted list to a numbered list for convenience. I am on no diabetes medications to mask the results here:

  1. My last HbA1C was 5.2 so I pass this test.
  2. My fasting plasma glucose is less than 100 typically so I pass this test.
  3. I have not had an OGTT (more on this to follow).
  4. I have none of the symptoms of hyperglycemia at all and I have had no blood sugar measurements of 200 or higher (or anywhere near that level) since I started Low Carb.

Oral Glucose Tolerance Test (OGTT)

I don’t know if I would pass an OGTT or not. I assume I would fail such at test in spite of losing 120 lbs, etc. The reason I assume I would fail is that I think part of being on a Low Carb ketogenic diet is that my body has developed peripheral insulin resistance.

Peripheral Insulin Resistance

PIR is a normal response to the ketogenic diet and happens as a response to lowered glucose availability. Here’s a mouse study which shows that Peripheral Insulin Resistance got worse under a ketogenic diet (Kinzig KP, Honors MA, Hargrave SL. Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet. Endocrinology. 2010;151(7): 3105-14.). The study measured:

After 8 wk of consuming chow or KD, caloric intake after peripheral or central insulin and insulin and glucose levels after a glucose challenge were assessed. In a separate group of rats, glucose and insulin responses to either a low- or high-carbohydrate test meal were measured. Finally, rats maintained on KD were switched back to a chow diet, and insulin sensitivity and glucose tolerance were evaluated to determine whether the effects of KD were reversible.

That answers the test that I would want to do to determine if I would pass an OGTT. What happened to the mice?

Maintenance on KD resulted in decreased sensitivity to peripheral insulin and impaired glucose tolerance.

So after 8 weeks of not eating carbohydrates the mice had trouble eating carbohydrates. Not much of a surprise there. It would take a deeper dive to see how much worse their PIR and IGT became.

Furthermore, consumption of a high-carbohydrate meal in rats that habitually consumed KD induced significantly greater insulin and glucose levels for an extended period of time, as compared with chow-fed controls.

So the mice over-reacted to carbohydrate meals by producing more glucose and insulin.

Responsivity to central insulin was heightened in KD rats and associated with increased expression levels of insulin receptor mRNA.

Not sure how to understand that if the mice were more insulin resistant. But was this effect a permanent change or was it temporary and a side effect of the diet itself?

Finally, returning to a chow diet rapidly reversed the effects of KD on insulin sensitivity and glucose tolerance. These data suggest that maintenance on KD negatively affects glucose homeostasis, an effect that is rapidly reversed upon cessation of the diet.

Although 8 weeks isn’t that long to a human it’s a long time to a mouse. I don’t know the scaling factor but it’s reasonable to assume it is years rather than the two months of the study.

So, if someone is concerned about whether or not they would pass an OGTT it seems like they probably could stop the ketogenic diet for some time (weeks maybe?) and then take the test. Most of us who do LC / Keto won’t be trying it anytime soon.

The fact is your doctor is not going to order an OGTT for you if you don’t fail one or more of the other numbers. In fact, if you fail the fasting blood sugar test the doctor might order you an HbA1C test for confirmation. And then, depending on other factors, may just decide to keep an eye on it.

DNA and Obesity/Diabetes

Am I Fat Because of My DNA?

There are a small number of people who may be fat due to faulty genetics (Lorenzo DN, Bennett V. Cell-autonomous adiposity through increased cell surface GLUT4 due to ankyrin-B deficiency. Proc Natl Acad Sci U S A. 2017;114(48):12743-12748.).

If not much of the fault can likely be blamed on your genes, but just how much can be? From (Sandholt CH, Vestmar MA, Bille DS, Borglykke A, Almind K, Hansen L, Sandbæk A, Lauritzen T, Witte D, Jørgensen T, Pedersen O, Hansen T. Studies of metabolic phenotypic correlates of 15 obesity associated gene variants. PLoS One. 2011;6(9)).

Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity.

BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4))).

Another study on obesity and genetics (Gudmar Thorleifsson, G Bragi Walters[…]Kari Stefansso. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nature Genetics volume 41, pages 18–24 (2009)).

Here’s another study on obesity and genetics (Sungshim Lani Park, Iona Cheng, Sarah A. Pendergrass, Anna M. Kucharska-Newton, Unhee Lim, Jose Luis Ambite, Christian P. Caberto, Kristine R. Monroe, Fredrick Schumacher, Lucia A. Hindorff, Matthew T. Oetjens, Sarah Wilson, Robert J. Goodloe, Shelly-Ann Love, Brian E. Henderson, Laurence N. Kolonel, Christopher A. Haiman, Dana C. Crawford, Kari E. North, Gerardo Heiss, Marylyn D. Ritchie, Lynne R. Wilkens, Loïc Le Marchand; Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations: The PAGE Study, American Journal of Epidemiology, Volume 178, Issue 5, 1 September 2013, Pages 780–790).

A similar paper on genetics and Type 2 Diabetes (McCarthy MI1, Zeggini E. Genome-wide association studies in type 2 diabetes. Curr Diab Rep. 2009 Apr;9(2):164-71).

Macronutrient Sensitivity and Genetics

My own AncestryDNA data shows an inconclusive result with one less of a carb seeker, one intermediate and one more of a carb seeker:

#ChromPositionSNP IDReliabilityGenotypePhenotypePopulationReferences
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker

This data is based on this study (Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake).

Signif. log(p) Effect Size / Odds Ratio






+ Strand




Trait Genes
9.4 0.22 (Fat)
[0.14-0.3] % decrease
rs838145 G G 0.46 FGF21 Dietary macronutrient intake
9 0.1 (Protein)
[0.061-0.139] % increase
rs1421085 C C 0.42 FTO Dietary macronutrient intake
6.52 0.23 (Carbohydrate)
[0.15-0.31] % increase
rs838145 G G 0.46 FGF21 Dietary macronutrient intake
6.15 0.22 (Carbohydrate)
[0.14-0.3] % increase
rs838147 A A 0.48 Intergenic Dietary macronutrient intake
5.7 0.27 (Carbohydrate)
[0.15-0.39] % increase
rs1549309 A A 0.17 Intergenic Dietary macronutrient intake
5.3 0.22 (Carbohydrate)
[0.12-0.32] % decrease
rs2840445 A A 0.27 Intergenic Dietary macronutrient intake
5.3 0.22 (Carbohydrate)
[0.12-0.32] % increase
rs8019546 A A 0.3 Intergenic Dietary macronutrient intake

AncestryDNA Raw Data Format

AncestryDNA Raw Data Format. From the site:

The information that you’ll receive with your AncestryDNA raw data will include the ‘rs’ ID where possible, chromosome, and the base pair position on the human reference genome (GRCh37). The genotype (the observed alleles at each position) will be provided on the forward strand. The raw DNA data provided has passed the AncestryDNA data quality filters.

An example of raw DNA data looks like:


It looks like from my data that tests about half of these genes. That’s unfortunate from a health perspective. Maybe the select other genes which are more genetically heritable?

SlimFast Keto Products

Here are another set of products I am going to avoid.

SlimFast Keto Meal Bars

I imagine they could have done worse than they did. But it’s hardly very good.

I have no clue how the label says free from artificial sweeteners but the ingredients list includes Erythritol. I suppose technically it’s considered to be a sugar alcohol and not an artificial sweetener…

Stevia is another “natural” sweetener.

Cultured Dextrose? That’s sugar.

If Ted Naiman and the Protein Leverage Hypothesis is true, we are people in search of protein. Eating products low in protein just makes us eat more.
I get the convenience part, but what’s wrong with real food?

How Metformin Works

Researchers have unlocked more about how Metformin works (
Zydrune Polianskyte-Prause, Tuomas A. Tolvanen, Sonja Lindfors, Vincent Dumont, Mervi Van, Hong Wang, Surjya N. Dash, Mika Berg, Jette-Britt Naams, Laura C. Hautala, Harry Nisen, Tuomas Mirtti, Per-Henrik Groop, Kristiina Wähälä, Jukka Tienari, and Sanna Lehtonen. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. The FASEB Journal 0 0:0. 15 Oct 2018).

Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication.

So not only does Metformin reduce the glucose production of the liver by downregulating GNG (Joseph A. Baur and Morris J. Birnbaum, Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo.Nature Medicinevolume 24, pages1384–1394 (2018)), it also increases the uptake of glucose in skeletal muscle and the kidneys.

Another paper on the action of Metformin (Baur JA, Birnbaum MJ. Control of gluconeogenesis by metformin: does redox trump energy charge?. Cell Metab. 2014;20(2):197-9.).

Here’s yet another paper on an effect of Metformin (Cheryl A. Collier, Clinton R. Bruce, Angela C. Smith, Gary Lopaschuk, and David J. Dyck. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle).

Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity.