Pathogenesis of Type 2 Diabetes Mellitus -RA Defronzo

[kokhongw]

Feb 2018
https://www.ncbi.nlm.nih.gov/books/NBK279115/

ABSTRACT
At least eight distinct pathophysiologic abnormalities have been associated with type 2 diabetes mellitus (T2DM). It is well established that decreased peripheral glucose uptake (mainly muscle) combined with augmented endogenous glucose production are characteristic features of insulin resistance.

Increased lipolysis, elevated free fatty acid levels, along with accumulation of intermediary lipid metabolites contributes to a further increase in glucose output, a reduction in peripheral glucose utilization, and impaired beta-cell function.

Compensatory insulin secretion by the pancreatic beta-cells may at first maintain normal plasma glucose levels, but beta-cell function is already abnormal at this stage, and progressively worsens over time.

Concomitantly, there is inappropriate release of glucagon from the pancreatic alpha-cells, particularly in the post-prandial period. It has been postulated that both impaired insulin and excessive glucagon secretion in type 2 diabetes are contributed to by the “incretin defect”, defined primarily as inadequate release or response to the gastrointestinal incretin hormones upon meal ingestion.

Moreover, hypothalamic insulin resistance (central nervous system) also impairs the ability of circulating insulin to suppress glucose production, and renal tubular glucose reabsorption capacity may be enhanced despite hyperglycemia in T2DM.

These pathophysiologic abnormalities should be considered for the treatment of hyperglycemia in patients with type 2 diabetes. For in-depth coverage of all aspects of Diabetes and Endocrinology visit www.endotext.org

 

[kokhongw]

This is the current textbook glucose centric view of T2D. So most pharma solutions are targeted at one or more of these abnormality...

 

[Guzzler]

I am interested in the increased glucagon secretion topic. Having learned that people can become glucagon resistant adds to my curiosity. Ben Bikman has a couple of YouTube talks on the subject but not enough (or not as much as Insulin) has been done on glucagon. Comments welcome.

 

[britishpub]

Concomitantly

I was doing fine until I reached that word

 

[kokhongw]

This might also be helpful...

 

[kokhongw]

So we can clearly see that the current treatment paradigm for T2D is primarily about treating hyperglycemia...nothing really about lowering insulin...

 

[DavidGrahamJones]

I was doing fine until I reached that word

Accompanying.

 

[kokhongw]

Liver as the main glucose supplier...

Approximately 85% of endogenous glucose production is derived from the liver, and the remaining amount is produced by the kidney (1,8,9). Approximately half of basal hepatic glucose production is derived from glycogenolysis and half from gluconeogenesis (9,10).

This helps us to understand how elevated Fasting glucose is affected by insulin resistance in the liver...

In type 2 diabetic subjects with mild to moderate fasting hyperglycemia (140-200 mg/dl, 7.8-11.1 mmol/L) basal hepatic glucose production [HGP] is increased by ~0.5 mg/kg.min. Consequently, during the overnight sleeping hours (2200 h to 0800 h), the liver of a 80-kg diabetic individual with modest fasting hyperglycemia adds an additional 35 g of glucose to the systemic circulation. The increase in basal HGP is closely correlated with the severity of fasting hyperglycemia (1,3,4,6,18,54,157-159,162). Thus, in type 2 diabetic subjects with overt fasting hyperglycemia (>140 mg/dl, 7.8 mmol/l), an excessive rate of hepatic glucose output is the major abnormality responsible for the elevated fasting plasma glucose concentration. The close relationship between fasting plasma glucose concentration and HGP has been demonstrated in numerous studies (164-166,170-174).

And here in the immediate following paragraph it is clear that researchers are well aware of the effects of hyperinsulinemia...

In the postabsorptive state, the fasting plasma insulin concentration in type 2 diabetic subjects is 2-4 fold greater than in nondiabetic subjects. Because hyperinsulinemia is a potent inhibitor of HGP (1,3,4-6,16,18,164,165,175), hepatic resistance to the action of insulin must be present in the postabsorptive state to explain the excessive output of glucose by the liver. Hyperglycemia per se also exerts a powerful suppressive action on HGP (15,167,175-177). Therefore, the liver also must be glucose resistance with respect to the inhibitory effect of hyperglycemia to suppress hepatic glucose output, and this has been well documented (15,167,178,179).

Putting these together, that is why keeping insulin low, eg intermittent fasting (dinner or breakfast) helps with improving fasting glucose level...

 

[kokhongw]

This last paragraph regarding insulin resistance in the liver is insightful on how our brain insulin signaling impairment may also affect glucose regulation...

More recent evidence has indicated that changes in hypothalamic insulin signaling may affect endogenous glucose production. The activation of the insulin receptor in the third cerebral ventricle is capable of suppressing glucose production, independent of circulating plasma insulin levels or other counter-regulatory hormones. Conversely, central antagonism of insulin signaling impairs the ability of circulating insulin to inhibit glucose production (6A). These observations have raised the possibility that hypothalamic insulin resistance contributes to hyperglycemia in type 2 diabetes.

 

[kokhongw]

Recently there has been much reported success with SGLT2 inhibitors...which reduce the reabsorption of glucose via our kidney. But I found it interesting that it only contributes 5-20% of glucose production...

The kidney also has been shown to produce glucose and estimates of the renal contribution to total endogenous glucose production have varied from 5% to 20% (8,9,195).

This is where adequate carbs reduction may have comparable or possibly better results...if only there were RCT comparing the 2...yet there's so much active objection against long term carbs reduction...but ironically no hesistation about complications from long term SGLT2-inhibitors prescriptions.

http://www.cclpharma.com/sglt2is-entering-new-era-insulin-independent-oral-anti-diabetics/

https://www.medscape.com/viewarticle/906054